HPN 2020 June/July

HOSPITAL PROFESSIONAL NEWS IRELAND

HPN June/July 2020 Issue 74 HOSPITALPROFESSIONALNEWS.IE

Ireland’s Dedicated Hospital Professional Publication

IN THIS ISSUE: Vit D and Covid 19 Professor Rose Anne Kenny Covid 19 Adapting to change Dr Diarmuid O’Shea

NOW A RECOMMENDED INITIAL REGIMEN1

Asthma Rates over 50 Dr Anne Nolan

Recommended as an initial regimen for most PLHIV (A1)* and as a good option for virologically suppressed patients who have no evidence of resistance to either drug Exclusions for treatment-naive patients: • HIV viral load >500,000 copies/mL • HBV co-infection • Where ART is to be started before the results of HIV genotype resistance testing for reverse transcriptase or HBV testing are available

EACS

Lung Health The biggest causalities Dr Aidan O’Brien

NOW A RECOMMENDED INITIAL REGIMEN2

ASCO 2020 New myeloma treatment Dr Paul Richardson

Recommended as an initial regimen for treatment-naïve patients and as a switch strategy for virologically suppressed patients Requirements for treatment-naive patients: • HBsAg negative • HIV viral load <500,000 copies/mL • CD4+ T-cell count >200 cells/µL

Blood clotting Professor James O’Donnell HIV Covid 19 impact on HIV

*Rating of recommendation: A=strong; Rating of evidence: I=data from randomised controlled trials; DOVATO is indicated for the treatment of HIV-1 in adults and adolescents above 12 years weighing at least 40 kg, with no known or suspected resistance to the integrase inhibitor class, or lamivudine.

Abridged Prescribing Information Dovato (dolutegravir 50mg/lamivudine 300mg) tablets See Summary of Product Characteristics (SmPC) before prescribing.

Presentation: Film-coated tablet containing dolutegravir sodium equivalent to 50 mg dolutegravir and 300 mg lamivudine debossed with “SV-137” on one face.

Indication: HIV-1 in adults & adolescents above 12 years of age weighing >40kg, with no known or suspected resistance to the integrase inhibitor class, or lamivudine.

Dosing: One tablet once daily with or without food. Use an additional 50mg tablet of dolutegravir approximately 12 hours after the dose of Dovato when co-administered with efavirenz, nevirapine, tipranavir/ritonavir, etravirine (without boosted PI), carbamazepine, oxcarbazepine, phenytoin, phenobarbital, St John’s Wort or rifampicin.

Elderly: Limited data in 65+ yrs. Not recommended in patients with creatinine clearance < 50 mL/min. Caution in severe hepatic impairment. Contraindications: Hypersensitivity to any ingredient. Co-administration with substrates of OCT-2 with narrow therapeutic windows, such as fampridine. Special warnings/precautions: Risk of hypersensitivity reactions. Discontinue dolutegravir and other suspect agents immediately. Risks of osteonecrosis, immune reactivation syndrome. Monitor LFTs in Hepatitis B/C co-infection and ensure effective Hepatitis B therapy. Caution with metformin: monitor renal function and consider metformin dose adjustment. Use with etravirine requires boosted PI or increased dose of dolutegravir. Use with Mg/Al-containing antacids requires dosage separation. Use with calcium, multivitamins or iron also requires dosage separation if not taken at the same time with food. Use with cladribine or emtricitabine not recommended. When possible, avoid chronic co-administration of sorbitol or other

Not an actual patient.

osmotic acting alcohols (see SmPC section 4.5). If unavoidable, consider more frequent viral load monitoring. Pregnancy/ lactation: The safety and efficacy has not been studied in pregnancy. Before initiating dolutegravir, women of childbearing potential (WOCBP) should undergo pregnancy testing. WOCBP who are taking dolutegravir should use effective contraception. Dolutegravir should not be used during the first trimester due to the potential risk of neural tube defects, unless there is no alternative.

Dolutegravir should only be used during the second and third trimester of pregnancy when the expected benefit justifies the potential risk to the foetus. Do not breast-feed.

Side effects: See SmPC for full details. Headache, GI disturbance, insomnia, abnormal dreams, depression, anxiety, dizziness, somnolence, rash, pruritus, alopecia, fatigue, arthralgia, myalgia, hypersensitivity, suicidal ideation or suicide attempt, hepatitis, blood dyscrasias, acute hepatic failure, pancreatitis, angioedema, rhabdomyolysis, lactic acidosis, peripheral neuropathy. Elevations of ALT, AST and CPK. MA Nr: EU/1/19/1370/001. MA holder: ViiV Healthcare BV, Huis ter Heideweg 62, 3705 LZ Zeist, Netherlands. Legal Category: POM A. Date of preparation of API: April 2020. Code: PI-5713. Further information available from GlaxoSmithKline, 12 Riverwalk, Citywest, Business Campus, Dublin 24. Tel: 01-4955000.

Adverse events should be reported to the Health Products Regulatory Authority (HPRA) using an Adverse Reaction Report Form obtained either from the HPRA or electronically via the website at www.hpra.ie. Adverse reactions can also be reported to the HPRA by calling (01) 6764971. Adverse events should also be reported to GlaxoSmithKline on 1800 244 255.

References: 1. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services. Dec 18, 2019. http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed April 2020 2. European AIDS Clinical Society Guidelines. Version 10.0. November 2019. https://www.eacsociety.org/files/2019_guidelines-10.0_final. pdf. Accessed April 2020

DOVATO is owned by or licensed to the ViiV Healthcare group of companies. ©2020 ViiV Healthcare group of companies or its licensor.

Date of preparation: June 2020. PM-IE-DLL-ADVT-200001

Irish Aids Day New Molecule identified for Diabetes Epilepsy: Discovery could lead to new therapies Dr Tobia Engel CPD: Stroke A Bleeding Dilemma Dr John Charles Corrigan

FOR YOURSELF, WOULD YOU CONSIDER

BOTH EFFICACY AND SAFETY?

Choose both efficacy and safety with ELIQUIS®

ELIQUIS is a factor Xa inhibitor that offers superior risk reduction in stroke and systemic embolism, with significantly less major bleeding vs. warfarin in non-valvular AF patients.1,* • Superiority demonstrated on stroke / systemic embolism vs. warfarin 1 • Superiority demonstrated on major bleeding vs. warfarin 1 ELIQUIS® (apixaban) 2.5 mg & 5 mg Film-coated Tablets Prescribing Information Consult Summary of Product Characteristics (SmPC) before prescribing PRESENTATION: Film-coated tablets; 5 mg and 2.5 mg apixaban. INDICATION: Prevention of stroke and systemic embolism in adults with non-valvular atrial fibrillation (NVAF) with one or more risk factors, such as prior stroke or transient ischaemic attack (TIA), age ≥ 75 years, hypertension, diabetes mellitus or symptomatic heart failure (NYHA Class ≥ II). Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults (see Special warnings and precautions for information on haemodynamically unstable PE patients). Prevention of venous thromboembolic events (VTE) in adults who have undergone elective hip or knee replacement surgery (2.5 mg only). DOSAGE AND ADMINISTRATION: Oral. Taken with water, with or without food. Prevention of stroke and systemic embolism in patients with NVAF: The recommended dose is 5 mg twice a day. In patients who meet at least two of the following criteria: serum creatinine ≥ 1.5 mg/dL (133 micromole/l), age ≥ 80 years, or body weight ≤ 60 kg the recommended dose is Eliquis, 2.5 mg twice daily. Patients with severe renal impairment (creatinine clearance 15-29 ml/min) should receive Eliquis 2.5 mg twice daily. Therapy should be continued long term. Treatment of DVT, treatment of PE and prevention of recurrent DVT and PE (VTEt): The recommended dose for the treatment of acute DVT and treatment of PE is 10 mg twice daily for the first 7 days followed by 5 mg twice daily. As per available medical guidelines, short duration of treatment (at least 3 months) should be based on transient risk factors (e.g. recent surgery, trauma, immobilisation). The recommended dose for the prevention of recurrent DVT and PE is 2.5 mg twice daily. When prevention of recurrent DVT and PE is indicated, the 2.5 mg twice daily dose should be initiated following completion of 6 months of treatment with Eliquis 5 mg twice daily or with another anticoagulant. The duration of overall therapy should be individualised after careful assessment of the treatment benefit against the risk for bleeding. Prevention of VTE (VTEp): elective hip or knee replacement surgery: The recommended dose is 2.5 mg twice a day. The initial dose should be taken 12 to 24 hours after surgery. Hip replacement surgery, the recommended duration of treatment is 32 to 38 days. Knee replacement surgery, the recommended duration of treatment is 10 to 14 days. Missed Dose for All Indications: If a dose is missed, Eliquis should be taken immediately and then continue with twice daily dose as before. Switching: switching treatment from parenteral anticoagulants to Eliquis (and vice versa) can be done at the next scheduled dose. These medicinal products should not be administered simultaneously. Switching treatment from VKA therapy to Eliquis: warfarin or other VKA therapy should be discontinued and Eliquis started when the international normalized ratio (INR) is < 2. Switching treatment from Eliquis to VKA therapy: administration of Eliquis should be continued for at least 2 days after beginning VKA therapy. After 2 days of co- administration of Eliquis with VKA therapy, an INR should be obtained prior to next scheduled dose of Eliquis. Co-administration of Eliquis and VKA therapy should be continued until the INR is ≥2. Renal impairment: No dose adjustment in mild or moderate renal impairment. Eliquis is to be used with caution in severe renal impairment (creatinine clearance 15-29 mL/min) as there may be an increased risk of bleeding. For the prevention of stroke and systemic embolism in patients with NVAF and severe renal impairment, patients should receive the lower dose of Eliquis 2.5 mg twice daily. Patients with NVAF and serum creatinine ≥ 1.5 mg/dL (133 micromole/L) associated with age ≥ 80 years or body weight ≤ 60 kg should also receive the lower dose of Eliquis 2.5 mg twice daily for stroke/systemic embolism prevention. In patients with creatinine clearance < 15 mL/min, or in patients undergoing dialysis, there is no clinical experience therefore Eliquis is not recommended. Hepatic impairment: Contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk. Not recommended in patients with severe hepatic impairment. Use with caution in patients with mild or moderate hepatic impairment (Child Pugh A or B). No dose adjustment is required in patients with mild or moderate hepatic impairment. Use with caution in patients with elevated liver enzymes (ALT/AST >2 x ULN) or total bilirubin ≥ 1.5 x ULN. Prior to initiating Eliquis, liver function testing should be performed. Catheter ablation (NVAF): Patients can continue Eliquis use while undergoing catheter ablation. Cardioversion (NVAF): Eliquis can be initiated or continued in NVAF patients who may require cardioversion. See SmPC for further details. Patients with NVAF and acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI): There is limited experience of treatment with apixaban at the recommended dose for NVAF patients when used in combination with antiplatelet agents in patients with ACS and/or undergoing PCI after haemostasis is achieved. See SmPC for further details Paediatric population: Eliquis is not recommended in children and adolescents below the age of 18. CONTRAINDICATIONS: Hypersensitivity to active substance or to excipients, active clinically significant bleeding, hepatic disease associated with coagulopathy and clinically relevant bleeding risk, lesion or condition if considered a significant risk factor for major bleeding, see SmPC for further details. Concomitant treatment with any other anticoagulant agent except under specific circumstances of switching anticoagulant therapy or when unfractionated heparin (UFH) is given at doses necessary to maintain an open central venous or arterial catheter or when UFH is given during catheter ablation for atrial fibrillation, see SmPC for further details. WARNINGS AND PRECAUTIONS: Haemorrhage risk: Carefully observe for signs of bleeding. Use with caution in conditions with increased risk of haemorrhage. Discontinue administration if severe haemorrhage occurs. An agent to reverse the anti-factor Xa activity of apixaban is available. For information on reversal and managing bleeding, see SmPC for further details. Interaction with other medicinal products affecting haemostasis: Concomitant treatment with any other anticoagulant is contraindicated (see contraindications). Concomitant use of Eliquis with antiplatelet agents increases the risk of bleeding. Care with concomitant SSRIs, SNRIs or NSAIDs, including GPIIb/IIIa receptor antagonists, dipyridamole, dextran or sulfinpyrazone) or thrombolytic agents. As such agents increase the bleeding risk, co-administration of these products with Eliquis is not recommended. See SmPC for further details. Due to an increased bleeding risk, concomitant treatment with any other anticoagulants is contraindicated, except under specific circumstances of switching anticoagulant therapy, when UFH is given at doses necessary to maintain an open central venous or arterial catheter or when UFH is given during catheter ablation for atrial fibrillation. Administration of activated charcoal reduces Eliquis exposure. Also see contraindications and special warnings and precautions section; Consult SmPC (contraindications, special warnings and precautions and drug interactions) for full details on interactions. PREGNANCY AND LACTATION: Pregnancy: Not recommended. Breastfeeding: Discontinue breastfeeding or discontinue Eliquis therapy. UNDESIRABLE EFFECTS: Increased risk of occult or overt bleeding from any tissue or organ, which may result in post haemorrhagic anaemia. The signs, symptoms, and severity will vary according to the location and degree or extent of the bleeding. Frequencies: common (≥ 100/1 to < 10/1); uncommon (≥ 1,000/1 to < 100/1); rare (≥ 10,000/1 to < 1,000/1); very rare (< 1/10,000); not known (cannot be estimated from the available data) Prevention of VTE in adult patients who have undergone elective hip or knee replacement surgery (VTEp): Common: anaemia, haemorrhage, haematoma, nausea, contusion. Uncommon: thrombocytopenia; Hypotension (including procedural hypotension); specific haemorrhage such as gastrointestinal, epistaxis, abnormal vaginal, urogenital, post procedural, incision site, operative; haematochezia.

Liver function test abnormal Rare :hypersensitivity, allergic oedema and anaphylaxis; specific haemorrhage such as eye (including conjunctival), gingival, rectal, muscle; haemoptysis. Prevention of stroke and systemic embolism in adult patients with NVAF, with one or more risk factors (NVAF): Common: anaemia, nausea, specific haemorrhage such as eye (including conjunctival), gastrointestinal, rectal; haemorrhage, haematoma, epistaxis, gingival bleeding, haematuria, contusion, hypotension acetylsalicylic acid. Following surgery, other platelet aggregation inhibitors are not recommended concomitantly with Eliquis.

In patients with atrial fibrillation and conditions that warrant mono or dual antiplatelet therapy, a careful assessment of the potential benefits against the potential risks should be made before combining this therapy with Eliquis. A clinical trial enrolled patients with atrial fibrillation with ACS and/or undergoing PCI and a planned treatment period with a P2Y12 inhibitor, with or without ASA, and oral anticoagulant (either apixaban or VKA) for 6 months. Concomitant use of ASA increased the risk of ISTH (International Society on Thrombosis and Hemostasis) major or CRNM (Clinically Relevant Non-Major) bleeding in apixaban-treated subjects. See SmPC for further details Use of thrombolytic agents for the treatment of acute ischemic stroke: Limited experience. Patients with prosthetic heart valves: safety and efficacy of Eliquis have not been studied in patients with prosthetic heart valves, with or without atrial fibrillation.

Therefore, the use of Eliquis is not recommended in this setting. Patients with antiphospholipid syndrome: Direct acting Oral Anticoagulants (DOACs), including Eliquis, are not recommended for patients with a history of thrombosis who are diagnosed with antiphospholipid syndrome (see SmPC for further details).

Surgery and invasive procedures: Discontinue at least 48 hours prior to elective surgery or invasive procedures with a moderate or high risk of bleeding. Discontinue at least 24 hours prior to elective surgery or invasive procedures with a low risk of bleeding. If surgery or invasive procedures cannot be delayed, appropriate caution should be exercised, taking into consideration an increased risk of bleeding. Eliquis should be restarted after the invasive procedure or surgical intervention as soon as possible provided the clinical situation allows and adequate haemostasis has been established. For patients undergoing catheter ablation for atrial fibrillation, Eliquis treatment does not need to be interrupted. Temporary discontinuation: Discontinuing anticoagulants, including Eliquis, for active bleeding, elective surgery, or invasive procedures places patients at an increased risk of thrombosis. Lapses in therapy should be avoided and if anticoagulation with Eliquis must be temporarily discontinued for any reason, therapy should be restarted as soon as possible. Spinal/epidural anaesthesia or puncture: Patients treated with antithrombotic agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal haematoma which can result in long- term or permanent paralysis. The risk of these events may be increased by the post- operative use of indwelling epidural catheters or the concomitant use of medicinal products affecting haemostasis. Indwelling epidural or intrathecal catheters must be removed at least 5 hours prior to the first dose of Eliquis. The risk may also be increased by traumatic or repeated epidural or spinal puncture. Patients are to be frequently monitored for signs and symptoms of neurological impairment (e.g., numbness or weakness of the legs, bowel or bladder dysfunction). If neurological compromise is noted, urgent diagnosis and treatment is necessary. Prior to neuraxial intervention the physician should consider the potential benefit versus the risk in anticoagulated patients or in patients to be anticoagulated for thromboprophylaxis. There is no clinical experience with the use of Eliquis with indwelling intrathecal or epidural catheters. See SmPC for further details. Haemodynamically unstable PE patients or patients who require thrombolysis or pulmonary embolectomy: Eliquis is not recommended as an alternative to unfractionated heparin in patients with pulmonary embolism who are haemodynamically unstable or may receive thrombolysis or pulmonary embolectomy since the safety and efficacy of Eliquis have not been established. Patients with active cancer: efficacy and safety of Eliquis in the treatment of DVT, treatment of PE and prevention of recurrent DVT and PE (VTEt) in patients with active cancer have not been established. Renal impairment: see dosage and administration section. Elderly patients: increasing age may increase haemorrhagic risk. Also, the co-administration of Eliquis with ASA in elderly patients should be used cautiously because of a potentially higher bleeding risk. Body weight: low body weight (< 60 kg) may increase haemorrhagic risk. Hepatic impairment: see dosage and administration section. Interaction with Inhibitors of CYP3A4 and P-gp: Not recommended with strong inhibitors of both CYP3A4 and P-gp These medicinal products may increase Eliquis exposure by 2-fold or greater in the presence of additional factors that increase Eliquis exposure (e.g. severe renal impairment) see SmPC for further details. Interaction with Inducers of CYP3A4 and P-gp: Eliquis should not be used for the treatment of DVT and PE in patients receiving concomitant systemic treatment with strong inducers of both CYP3A4 and P-gp since efficacy may be compromised. Concomitant systemic treatment with strong inducers of both CYP3A4 and P-gp, Eliquis should be used with caution for the prevention of VTE in elective hip or knee replacement surgery, for the prevention of stroke and systemic embolism in patients with NVAF and for the prevention of recurrent DVT and PE, though no dose adjustment for Eliquis is required during concomitant therapy with such medicinal products. Hip fracture surgery: Eliquis has not been studied in clinical trials in patients undergoing hip fracture surgery. Therefore, it is not recommended in these patients. Laboratory parameters: Clotting tests (PT, INR, and aPTT) are affected by the mechanism of action of apixaban. Changes observed at the expected therapeutic dose are small and subject to a high degree of variability, see SmPC for further details. Information about excipients: Eliquis contains lactose. Patients with galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take Eliquis. DRUG INTERACTIONS: Eliquis should be used with caution when co-administered with SSRIs/SNRIs, NSAIDs, ASA and/or P2Y12 inhibitors because these medicinal products typically increase the bleeding risk. There is limited experience of co-administration with other platelet aggregation inhibitors (such as (including procedural hypotension); Gamma-glutamyltransferase increased. Uncommon: hypersensitivity, allergic oedema and anaphylaxis; specific haemorrhage such as brain, intracranial, intraspinal, intra-abdominal, abnormal vaginal, urogenital, mouth, haemorrhoidal, traumatic, post procedural, incision site; haemoptysis, haematochezia, thrombocytopenia, Liver function test abnormal. Rare: specific haemorrhage such as respiratory tract, retroperitoneal. Treatment of DVT and PE, and prevention of recurrent DVT and PE (VTEt): Common: anaemia, nausea, skin rash, haemorrhage, haematoma, epistaxis; specific haemorrhage such as mouth, gastrointestinal, rectal; gingival bleeding, haematuria, abnormal vaginal, urogenital, contusion, gamma-glutamyltransferase increased, alanine aminotransferase increased; thrombocytopenia. Uncommon: Hypersensitivity, allergic oedema and Anaphylaxis, specific haemorrhage such as eye (including conjunctival), haemorrhoidal, traumatic, post procedural, incision site; haemoptysis, muscle, haematochezia, Liver function test abnormal. Rare: specific haemorrhage such as brain, intracranial, intraspinal, respiratory tract. Refer to SmPC for all other adverse events, including other types of haemorrhage. LEGAL CATEGORY: POM. MARKETING AUTHORISATION NUMBER: EU/1/11/691/002-3, EU/1/11/691/008, EU/1/11/691/014 PACKAGE QUANTITIES: Carton of 20 film-coated tablets 2.5 mg, 60 film-coated tablets 2.5 mg, 56 film-coated tablets 5 mg, 28 film- coated tablets 5 mg. MARKETING AUTHORISATION HOLDER: Bristol-Myers Squibb/Pfizer EEIG LOCAL REPRESENTATIVE IN IRELAND: Bristol-Myers Squibb Pharmaceuticals uc, Plaza 254, Blanchardstown Corporate Park 2, Dublin 15, D15 T867, Ireland.. Tel: 01 483 3625 DATE OF LAST REVISION: March 2020 ADDITIONAL INFORMATION AVAILABLE ON REQUEST Mercury Internal Ref. no: 432IE2002206-01

Adverse events should be reported. Reporting forms and information can be found at: Ireland - via HPRA Pharmacovigilance at www.hpra.ie Adverse events should also be reported to Bristol Myers Squibb via medical.information@bms.com or 1 800 749 749 (Ireland)

*with one or more risk factors, such as prior stroke or transient ischaemic attack (TIA); age≥ 75 years; hypertension; diabetes mellitus; symptomatic heart failure (NYHA Class ≥ II) AF = Atrial Fibrillation. Reference: 1. Granger CB et al. N Engl J Med 2011; 365: 981–992.

Date of approval: June 2020 Job code: PP-ELI-EUR-1046; PP-ELI-IRL-0418 www.eliquis.ie

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June/July Issue Issue 74

Contents

Foreword

New Health Minister announced P4

Editor Ireland’s new Health Minister, Wicklow TD Stephen Donnelly, who replaces Simon Harris has said that the Sláintecare plan remains the main route to reform of the healthcare system and that the move towards universal healthcare had to be accelerated in response to the Covid-19 crisis.

Ireland’s Emer Cooke appointed to the European Medicines Agency P6 Royal College of Physicians Registrar talks about life post Covid-19 P12

6

Certainly Covid-19 and the challenges it has brought, and continues to bring, is a daunting prospect for any new government. Coronavirus had been a complicating factor for a healthcare system already facing major challenges Stephen Donnelly told Newstalk’s Pat Kenny Show.

Lung Health to become one of the biggest Pandemic casualties P18

His appointment has been welcomed by representative bodies who will be looking to engage with him on the numerous issues facing the health service outside of the current global pandemic.

12

Research presented on blood clotting P26 Irish Medication Safety Network updates P32

For almost a year, there has been a deliberate decision from Government to provide no new funding to the HSE for new medicines, says IPHA.

REGULARS Educational: HIV in Ireland P28

26

“The HSE has asked and was refused. This has created a backlog of at least 18 new medicines still unavailable for patients, despite having met Irish clinical effectiveness and value for money tests.

CPD: Stroke Bleeding Dilemma P33 Feature: Diabetes P40 Clinical Profiles P46 Hospital Professional News is a publication for Hospital Professionals and Professional educational bodies only. Subscription rate for Hospital Professional News ¤60 plus vat per year.

All rights reserved by Hospital Professional News. All material published in Hospital Professional News is copyright and no part of this magazine may be reproduced, stored in a retrieval system of transmitted in any form without written permission.

IPN Communications Ltd have taken every care in compiling the magazine to ensure that it is correct at the time of going to press, however the publishers assume no responsibility for any effects from omissions or errors.

PUBLISHER IPN Communications Ireland Ltd Clifton House, Lower Fitzwilliam Street, Dublin 2 | (01) 669 0562 GROUP DIRECTOR Natalie Maginnis n-maginnis@btconnect.com

In other news, the draft Programme for Government – Our Future, was published in June, leaving unresolved the funding crisis for new medicines, according to the Irish Pharmaceutical Healthcare Association (IPHA), which represents the international researchbased biopharmaceutical industry.

32

BUSINESS & SALES MANAGER Siobhan Buchanan-Johnston siobhan@hospitalprofessionalnews.ie

SALES & MARKETING EXECUTIVE Amy Evans | amy@ipn.ie EDITORIAL editorial@hospitalprofessionalnews.ie

ACCOUNTS Rachel Wilson cs.ipn@btconnect.com CONTRIBUTORS

“The funding of new medicines is in crisis,” said Oliver O’Connor, CEO of IPHA. “The new Programme for Government is totally silent on funding new medicines. Without a change in direction from Government, the HSE is still effectively prohibited from paying for new medicines for patients. You can read more about this on page 5.

This issue also carries detail on some of the most recent and updated research from TILDA on pages 10-11, including a look at new international collaborative study between Trinity and the University of Liverpool, published in the British Medical Journal which offers fresh insight into COVID-19’s impact across countries, and the factors that influence its severity.

The features in this June/July double issue look at HIV infections and Diabetes, whilst Dr John Corrigan examines the bleeding dilemma posed by Stroke in our Continuing Professional Development series. Next month’s issue is the annual Peer Review so don’t miss it!

Stay safe.

Dr John Corrigan

DESIGN DIRECTOR Ian Stoddart Design

HOSPITALPROFESSIONALNEWS.IE

@HospitalProNews HospitalProfessionalNews

HOSPITAL PROFESSIONAL NEWS IRELAND Ireland’s Dedicated Hospital Professional Publication HOSPITALPROFESSIONALNEWS.IE | HPN • JUNE/JULY 2020

4 News

Sláintecare remains main route to reform – new Health Minister New Minister for Health Stephen Donnelly

The 59-year-old Cork native was elected at a special meeting of the Irish parliament in Dublin. He has been the leader of the Fianna Fáil party since 2011. As Health Minister in 2004, he became the first national government minister in any part of the world to introduce a workplace smoking ban, which also banned the public from lighting up in pubs.

Fianna Fáil leader Mícheál Martin has been elected Ireland's Taoiseach after rival parties voted to endorse a coalition government. Memberships of three parties agreed to work together putting centre right party Fianna

Fáil, centre party Fine Gael and the Green party in coalition with each other.

Wicklow TD Stephen Donnelly will replace Simon Harris as Minister for Health after Taoiseach Micheál Martin unveiled details of the new coalition Cabinet during a sitting of the Dáil in Dublin’s Convention Centre.

The new Taoiseach has said the fight against Covid-19 will be his government's first priority.

Simon Harris will now take the role of Minister for Higher Education, Innovation and Research.

Mr Donnelly said that the Sláintecare plan remains the main route to reform of the healthcare system and that the move towards universal healthcare had to be accelerated in response to the Covid-19 crisis.

Coronavirus had been a complicating factor for a healthcare system already facing major challenges Stephen Donnelly told Newstalk’s Pat Kenny Show.

Dr Donal O'Hanlon, President of the Irish Hospital Consultants Association, has welcomed the formation of the new Government and the appointment of Mr Stephen Donnelly as Minister for Health.

He said that the IHCA looks forward to engaging constructively with the Minister on the development and implementation of practical, workable solutions to address the significant challenges which are impacting on the country's health services.

HOSPITAL PHARMACISTS CONGRESS 2021 The 25th EAHP (European Association of Hospital Pharmacists) Anniversary Congress was postponed due to a force majeure situation and has been rescheduled to 24-26 March 2021 to take place in Vienna, Austria.

EAHP took many things into consideration regarding the postponement, with safety being the number one priority. In addition, it is most probable that many hospital pharmacists and other healthcare professionals will not be permitted to attend events this year as all hospitals will either still be caring for patients infected by COVID-19 along with all patients in general or recovering from the pandemic that has affected us all in some way.

Registrations already paid for will not be refunded but will be transferred to the Vienna congress.

The program theme and topics will remain the same with the exception of adding some relevant new session topics. Visit www.eahp/eu for more details.

Roscommon Adopt Photo Triage The Plastic Surgery Department at Roscommon University Hospital has been using a ‘photo triage’ process to identify patients who require an urgent consultation, to replace face-to-face consultations during the COVID-19 pandemic.

Deidre Jones, Consultant Plastic and Reconstructive Surgeon said, “When our ‘See and Treat’ skin cancer clinics were suspended due to COVID-19, we set up a new pathway to identify patients who required urgent consultation.

Ms Deirdre Jones, Consultant Plastic and Reconstructive Surgeon at Roscommon University Hospital using photo triage to identify patients who require an urgent consultation

JUNE/JULY 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

“By telephoning patients directly, asking them a few key questions and requesting that they email

a good quality photograph of their skin lesion to a secure and dedicated email address, we have been able to photo triage over 400 patients in the past few months.As we start to reintroduce services to the hospital, it will no longer be possible to have large numbers of patients attending our clinics due to social distancing and infection control requirements. We plan to continue with and refine the photo triage process because it is so convenient for patients and will allow us to continue to prioritise those who need to be seen urgently first.”

News

5

Unresolved Funding for new Medicines The ‘Programme for Government – Our Shared Future’, is welcome in many respects but it leaves unresolved the funding crisis for new medicines, according to the Irish Pharmaceutical Healthcare Association (IPHA), which represents the international research-based biopharmaceutical industry.

For almost a year, there has been a deliberate decision from Government to provide no new funding to the HSE for new medicines. The HSE has asked and was refused. This has created a backlog of at least 18 new medicines still unavailable for patients, despite having met Irish clinical effectiveness and value for money tests.

“The funding of new medicines is in crisis,” said Oliver O’Connor, CEO of IPHA. “The new Programme for Government is totally silent on funding new medicines. Without a change in direction from Government, the HSE is still effectively prohibited from paying for new medicines for

patients. The result is that patients in Ireland are among the last in western Europe to access new innovative treatments. That means doctors are unable to prescribe the newest and best medicines for patients with serious illnesses like cancer, stroke and heart disease.

This Programme for Government leaves patients and doctors still waiting,” he added.

IPHA has said it is ready and willing to co-fund new medicines in the October Budget. “In its first Budget, the new Government must put new funding for new medicines on the table. That can be the basis for a new Agreement – a joint funding model recognising that both industry and the State share a responsibility to give patients the same treatment options as their peers in western Europe.

“With the current Agreement on pricing and supply of medicines set to expire, we are working on a co-funding model in which both industry and the State would agree to jointly fund new

medicines. That’s the fairest way to ensure patients get timely access to the best medicines,” said Mr O’Connor.

IPHA said it would study closely the mandate of the “National Medicines Agency”. “The National Centre for Pharmacoeconomics already professionally evaluates new medicines and the HSE implements a Medicines Management Programme. But without new Government funding, the experience is that medicines simply back up inside the HSE. The same thing will happen in a National Medicines Agency if funding is not provided. Patients will still wait for treatment options that are available elsewhere in Europe.”

IPHA said the Government should recognise the potential of the biopharmaceutical industry, whose footprint in Ireland creates some 45,000 jobs, to enable “reform and renewal” in society.

Biopharmaceutical companies have shown how essential they

are in supplying medicines to patients during COVID-19 and keeping manufacturing sites fully functional. Now, as Ireland targets economic recovery, the industry can be an engine for growth.

IPHA welcomed the promised “high-level review of the Irish economy led by the Department of the Taoiseach”, saying the biopharmaceutical industry has a “key role” in preventing and tackling “future public health challenges”. IPHA said the promised “modern eHealth and ICT infrastructure” could help in designing more effective medicines and tracking patient outcomes.

IPHA welcomed the focus on rare diseases and said the political will to reimburse medicines to treat them must be shown from Budget 2021.

It welcomed the planned rollout of the flu vaccine to more people without charge and urged the promotion of childhood vaccinations.

Air Hubs to secure Pharmacy Supply Chain Medicines for Ireland (MFI), the Irish pharmaceutical trade association and the supplier of the majority of medicine in Ireland to the HSE and patients directly, has called for the creation of dedicated air freight hubs across the European Union (EU) to act as primary import and export points for medicines, active pharmaceutical ingredients, intermediates, key starting materials and medical equipment.

Commenting after a Dáil discussion on health and COVID-19, MFI chairperson, David Delaney said, “Pharmaceutical manufacturers rely on capacity in passenger flights to move medicines and ingredients rapidly and securely. With the spread of COVID-19, we’ve seen a dramatic reduction in passenger flights that normally carry pharmaceutical goods. We are recommending that EU authorities create dedicated air freight hubs to ensure there is enough capacity to cover the needs of the supply chain across Europe to mitigate the dramatic reduction of passenger flights.

Medicines for Ireland Chair David Delaney

“Similar provision is required in countries such as India and China which are major exporters of medicines to the EU and due to the global nature of the medicines supply chain, it is vital that an integrated international approach is taken to air freight for essential medicines. We’re asking the Irish Government and policy makers to proactively engage with their European counterparts to secure viable and affordable air freight

access for medicines in and out of Europe.

“We’re continuing to work proactively with Government and key policy makers on aspects of policy to ensure round the clock continuity of supply in Ireland.

We’re also communicating on daily basis with the Department of Health and the Health Products Regulatory Authority (HPRA) as well as the HSE, EU Commission and all relevant EU institutions

to ensure a solution focused approach is taken to secure a stable supply of medicines to the Irish market.”

MFI member companies which include Accord Healthcare; Aribamed; Clonmel Healthcare; Consilient Health; Fannin; Fresenius-Kabi; Mylan; Pinewood; Rowa; and Teva, contribute significantly to Ireland’s ¤40 billion annual pharmaceutical and device exports.

HOSPITALPROFESSIONALNEWS.IE | HPN • JUNE/JULY 2020

6 News

Emer Cooke to head up EMA The European Medicines Agency (EMA), Executive Director, Emer Cooke

The European Medicines Agency (EMA) Management Board has nominated Emer Cooke as the new Executive Director of the Agency. At an extraordinary virtual session on 25 June, the Board selected Emer Cooke from a shortlist of candidates created by the European Commission.

Emer has now become the first woman to lead the powerful regulatory body. The appointment comes at a crucial time for the agency, as it may take up an increasing role in securing supplies of medicines and streamlining research into new drugs as the European Union bids for increased powers in health to avoid pharmaceutical shortages and improve its future pandemic response.

Ms Cooke will now be invited to give a statement to the European Parliament’s Committee on Environment, Public Health and Food Safety (ENVI) on 13 July 2020. The

appointment of the new Executive Director will only be made after that meeting.

Emer Cooke, an Irish national, is currently the Director of the Regulation and Prequalification Department at the World Health Organization (WHO) in Geneva, a position she has held since November 2016. In this role she leads on WHO’s global work on health technologies regulation, including prequalification, regulatory systems strengthening and safety activities. Her role also covers assurance of quality, safety, efficacy and performance of health technologies in close conjunction with member states and international partners.

Ms Cooke has 30 years’ experience in international regulatory affairs, 18 years of which were in leadership roles. She worked for the pharmaceutical unit of the European Commission from 1998 to 2002 and at EMA between 2002 and 2016, where she held positions including Head of Inspections and Head of International Affairs.

Ms Cooke holds a degree in pharmacy from Trinity College, Dublin in Ireland. She has additional Masters degrees in Science and in Business Administration, also from Trinity.

National Treatment Purchase Fund ‘could reach 1M’ The Irish Hospital Consultants Association (IHCA) has warned of unprecedented challenges in the months ahead unless realistic practical plans are developed and implemented urgently to expand our public hospital capacity and community step down services to provide care to non-COVID and COVID-19 patients.

The IHCA has highlighted concerns that Ireland’s health system could soon see up to 1 million people on a National Treatment Purchase Fund (NTPF) waiting list, as 39,683 have now been added to the NTPF lists since the start of 2020.

Despite a decade of denial, it is clear Ireland has one of the lowest numbers of public hospital beds and hospital consultants in the

EU, adjusted for population levels.

According to hospital consultants, while the immediate threat of COVID-19 has reduced, Ireland’s acute public hospitals continue to suffer from significant capacity deficits, making it imperative that election promises to hire more consultants and open more public hospital and community beds are now acted upon by the next Government.

Previously closed acute hospital beds, that were reopened in the past 3 months to cater for the Covid-19 crisis, need to remain open on a permanent basis.

The Government also needs to fund between 1,500 and 2,000 additional intermediate care or step-down beds, which are being commissioned. These beds are required to urgently free up public

hospital capacity to treat patients suffering from delayed care due to the pandemic and those on legacy waiting lists.

The recommendation, a decade ago, to double the number of public hospital ICU beds was not implemented as quickly as it should have been and must be achieved on a sustainable basis before the winter. It is essential that the hundreds of improvised ICU beds open in recent months are now fully equipped and staffed on a permanent basis as recommended in 2010.

Consultants have cited reports that several hospitals are seeing a reduction in general bed capacity availability, with Limerick, Kilkenny and the Children's Hospital Tallaght, listed by the HSE as

having no vacant beds for patients on Tuesday of this week.

The consultants’ warning comes as latest waiting list figures (for May 2020) show: • 808,447 people are now waiting on some form of NTPF waiting list, an increase of 39,683 since the start of 2020; • 575,863 outpatients nationally are waiting to be seen by a consultant, an increase of 8,534 (1.5%) on last month and of 22,429 (4.1%) since the start of the year; with • 86,946 now wating for inpatient/ day case treatment, an increase of 603 or 0.7% on last month but an additional 20,241 (30.3%) patients since the start of the pandemic in March.

PMI Women in Leadership – July 20 | Date: 16th July, 2020 Due to the ongoing Cornavirus restrictions, The Pharmaceutical Manufacturers Institute (PMI) are moving their popular Women in Leadership online for the foreseeable future. The next WiL event will take place on Thursday July 16th at 1pm, and special guest will be Liz Henderson, Regional Vice President, APC with Merck Group. The Women in Leadership series is proudly sponsored by Star Medical Ireland.

JUNE/JULY 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

A new option in HIV-1

Make Doravirine a Part of Every Day DELSTRIGO® (100 mg doravirine/300 mg lamivudine/300 mg tenofovir disoproxil fumarate, equivalent to 245 mg of tenofovir disoproxil) is indicated for the treatment of adults infected with HIV-1 without past or present evidence of resistance to the NNRTI class, lamivudine, or tenofovir.1 PIFELTRO® (doravirine) is indicated, in combination with other antiretroviral medicinal products, for the treatment of adults infected with HIV-1 without past or present evidence of resistance to the NNRTI class.2 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions.

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information.

Healthcare professionals are asked to report any suspected adverse reactions.

See section 4.8 of the SPC for how to report adverse reactions.

ABRIDGED PRODUCT INFORMATION Refer to Summary of Product Characteristics before prescribing. PRESENTATION Pifeltro: film-coated tablet containing 100 mg doravirine. Delstrigo: film-coated tablet containing 100 mg doravirine, 300 mg lamivudine and 300 mg tenofovir disoproxil fumarate, equivalent to 245 mg of tenofovir disoproxil. INDICATIONS Pifeltro: For use in combination with other antiretrovirals, for the treatment of HIV-1 without past or present evidence of resistance to non-nucleoside reverse transcriptase inhibitors (NNRTI). Delstrigo: For the treatment of HIV-1 without past or present evidence of resistance to NNRTIs, lamivudine or tenofovir. DOSAGE AND ADMINISTRATION Therapy should be initiated by a physician experienced in HIV infection management.

Pifeltro: One 100 mg tablet once daily. Delstrigo: One 100/300/245 mg tablet once daily. Pifeltro and Delstrigo: If co-administered with rifabutin or other moderate CYP3A inducers, increase doravirine dose to 100 mg twice daily (12 hours apart). Pifeltro: Elderly: No dose adjustment necessary. Renal impairment: No dose adjustment necessary. Hepatic impairment: mild to moderate: no dosage adjustment required; severe: use with caution. Delstrigo: Elderly: Special care advised. Renal impairment: estimated creatinine clearance (CrCl) ≥ 50 mL/min: no dose adjustment necessary; estimated CrCl <50 mL/min: not recommended. Hepatic impairment: mild to moderate: no adjustment required; severe hepatic: use with caution. CONTRAINDICATIONS Hypersensitivity to the active substance or excipients Co-administration with strong CYP3A inducers. PRECAUTIONS AND WARNINGS A residual risk of sexual transmission of HIV-1 cannot be excluded and precautions should be taken in accordance with national guidelines. Use with CYP3A inducers may reduce the exposure of doravirine. Autoimmune disorders (such as autoimmune hepatitis) and immune reactivation syndrome have been reported in patients treated with combination antiretroviral therapy which may require investigation and treatment. Contains lactose monohydrate. Delstrigo: Post-treatment exacerbation of HBV (including hepatic decompensation and liver failure) have been reported in patients co-infected with HIV-1 and HBV following discontinuation of lamivudine or tenofovir disproxil. Monitor patients co-infected with HIV-1 and HBV after discontinuation of Delstrigo and if appropriate initiate anti-HBV therapy. Renal impairment, including acute renal failure and Fanconi syndrome have been reported with tenofovir disoproxil. Assess estimated CrCl prior to initiation and during therapy. In patients at risk of renal dysfunction, serum phosphorus, urine glucose, and urine protein should also be assessed. Discontinue therapy if estimated CrCl declines below 50 mL/min. Avoid with concurrent or recent use of nephrotoxic medicinal products (e.g. high-dose or multiple NSAIDs). Evaluation of renal function is recommended for persistent or worsening bone pain, pain in extremities, fractures, and/or muscular pain or weakness. Assessment of bone mineral density should be considered for patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Hypophosphatemia and osteomalacia secondary to proximal renal tubulopathy should be considered in patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms. Doravirine/lamivudine/tenofovir disoproxil must not be co-administered with other medicinal products containing lamivudine, tenofovir disoproxil, or tenofovir alafenamide or with adefovir dipivoxil. Doravirine/lamivu-

dine/tenofovir disoproxil should not be administered with doravirine unless needed for dose adjustment (e.g. co-administered with rifabutin). Drug interactions: Refer to SmPC for full information on drug interactions. Pifeltro and Delstrigo: Doravirine is metabolized primarily by CYP3A. Do not co-administer with strong CYP3A enzyme inducers. If co-administration with rifabutin or other moderate CYP3A inducers cannot be avoided, increase doravirine dose to 100 mg twice daily (taken 12 hours apart). Use with caution when co-administering doravirine with medicinal products that are sensitive CYP3A substrates that have a narrow therapeutic window (e.g., midazolam, tacrolimus and sirolimus). Delstrigo: Do not administer with other antiretroviral medicinal products. Co-administration of doravirine/lamivudine/tenofovir disoproxil with medicinal products that reduce renal function or compete for active tubular secretion may increase serum concentrations of lamivudine. Co-administration of doravirine/lamivudine/tenofovir disoproxil with medicinal products that reduce renal function or compete for active tubular secretion via OAT1, OAT3 or MRP4 may increase serum concentrations of tenofovir. Avoid with concurrent or recent use of nephrotoxic medicinal products. Pregnancy and Lactation: Pifeltro and Delstrigo: Avoid use during pregnancy. An Antiretroviral Pregnancy Registry has been established. Breastfeeding is not recommended.

SIDE EFFECTS Refer to SmPC for complete information on side-effects.Pifeltro and Delstrigo: Common: abnormal dreams, insomnia, headache, dizziness, somnolence, nausea, diarrhoea, abdominal pain, flatulence, vomiting, rash, fatigue alanine aminotransferase increased. Uncommon: hypophosphataemia, nightmare, depression, suicidal ideation, paraesthesia, asthenia. Rare: hypomagnesaemia, blood creatine phosphokinase increased. Delstrigo: Common: cough, nasal symptoms, alopecia, muscle disorders, fever. Uncommon: neutropenia, anaemia, thrombocytopenia, pancreatitis, rhabdomyolysis, proximal renal tubulopathy (including Fanconi syndrome), aspartate aminotransferase increased. Rare: lactic acidosis, hepatitis, angioedema, myopathy, acute renal failure, renal failure, acute tubular necrosis, nephritis (including acute interstitial) and nephrogenic diabetes insipidus. Very Rare: pure red cell aplasia, peripheral neuropathy (or paraesthesia). PACKAGE QUANTITIES Bottle of 30 tablets. Legal Category: POM. Marketing Authorisation numbers: Pifeltro: EU/1/18/1332/001, Delstrigo: EU/1/18/1333/001. Marketing Authorisation Holder: Merck Sharp & Dohme B.V., Waarderweg 39, 2031 BN Haarlem, The Netherlands. Date of revision: September 2019. © Merck Sharp & Dohme Ireland (Human Health) Limited 2019.

All rights reserved. Further information is available on request from: MSD, Red Oak North, South County Business Park, Leopardstown, Dublin 18, D18 X5K7 or from www.medicines.ie. Date of Preparation: June 2020. IB/0007/0008.

References: 1. DELSTRIGO Summary of Product Characteristics, December 2019. 2. PIFELTRO Summary of Product Characteristics, November 2019.

Adverse events should be reported. Reporting forms and information can be found at www.hpra.ie.

Adverse events should also be reported to MSD (Tel: 01-2998700)

Red Oak North, South County Business Park, Leopardstown, Dublin D18 X5K7 Ireland

IE-DOV-00016

PIFELTRO® ▼ (Doravirine) DELSTRIGO® ▼ (Doravirine/Lamivudine/Tenofovir disproxil fumarate)

8 Pharmacy

Make best use of Hospital Pharmacy Dr Matthew Jones, Lecturer in Pharmacy Practice

hospital discharge. After using the service, patients said the helpline service was quicker to access than their GP and often more helpful.

But although 52% of NHS Trusts currently provide a medicines helpline, few discharged patients seem to know of their existence, resulting in extremely low usage.

Matt Williams, the Bath PhD student who led the research said: “A typical hospital that discharges over 100 patients every day will have 30 to 40 patients with a potential need to call the helpline, yet they might get just one call a day.

Recent research suggests the best medicine-related support comes from hospital pharmacists, yet few discharged patients use helplines set up for this purpose.

Leaving hospital can be a confusing and sometimes risky time for patients who take medication, with an estimated 44% experiencing medicinerelated problems once they get home. New research suggests the

most helpful and timely medicinerelated support is provided by hospital pharmacists.

The University of Bath study explored the experiences of 40 patients or their carers using various hospital-based telephone medicines information services.

It found that patients who have called a service regard it as uniquely placed to answer medication queries arising after

“If people don’t know the service exists, they either do nothing when problems arise or they go to their GP, use the emergency services or turn to the people around them or Google for non-expert and potentially unreliable advice. Yet they could resolve their problem with a simple phone call, which is quicker and easier for both the person and the NHS.” Dr Matthew Jones, lecturer in pharmacy practice at the university, explained that patients often experience big changes to

their medicine regimen when they are discharged from hospitals, and it’s common for them to find there are gaps in their knowledge.

He said: “They might have questions about side effects, correct dosage or potential interactions between medications.

Getting the right information can help them avoid harm. It can also draw attention to mistakes that have been made with their medicines.”

A second study from the Bath team finds that hospital pharmacists who provide a hospital medicines helpline service are aware that it is a valuable resource for patients but regard it as under-resourced.

“There is concern among pharmacists that if they advertise the service more widely, they will not be able to cope with the influx of enquiries. To benefit as many patients as possible, pharmacists need guarantees they will be given time to help everyone who calls” said Dr Jones.

Dr Jones said: “It’s important that all patients discharged from hospital can easily get timely and expert advice about their medicines. Different areas currently do this in different ways, which is one reason why the public doesn’t know about the services that are there to help them. In addition, the government recently announced a new Discharge Medicines Service, which will allow people to seek help from their community pharmacy.”

Memorandum of Understanding for Pharmacy The PSI–the pharmacy regulator and Sport Ireland have signed a Memorandum of Understanding (MOU) that will assist joint working between the agencies, particularly when there are overlapping interests or areas of mutual concern.

The MOU has been welcomed by the Minister for Media, Tourism, Arts, Culture, Sport and the Gaeltacht, Catherine Martin TD, “We have seen over recent weeks and months that sport and physical activity plays an

important role in our daily lives.

As competitive sport resumes as we enter phase 3 of the Covid-19 restrictions, we need to make sure that our collective fight against doping in sport continues to be relentless. The signing of the MOU between Sport Ireland and the PSI is a positive step for anti-doping in Ireland and an excellent example of agencies of the state working together for the greater good.”

In signing the MOU, John Treacy, CEO of Sport Ireland, and PSI Registrar/Chief Officer Niall Byrne

JUNE/JULY 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

stated that the memorandum focuses on their common purpose as public bodies. It provides a clear framework that governs and strengthens the working relationship between the organisations, both of which are tasked with upholding standards of conduct and good practice in the public interest.

“Our role in the PSI is to protect, maintain and promote the health and safety of the public by ensuring that the standards of practise and the reputation

of the profession of pharmacy are upheld. I am pleased that the PSI can engage with Sport Ireland to exchange information that supports the wider public interest. This includes ensuring that those who are registered with the PSI conduct themselves in a competent and ethical manner, and in doing so contribute to reducing the scope for harmful and improper use of substances in sport,” Niall Byrne added.

Research

9

Vitamin D and Covid-19 Could lack of vitamin D and ultraviolet be linked to COVID-19 mortality in northerly latitudes?

A new international collaborative study between Trinity and the University of Liverpool, published in the British Medical Journal offers fresh insight into COVID-19’s impact across countries, and the factors that influence its severity.

Professor Rose Anne Kenny, Principal Investigator of TILDA

The study reports COVID-19 mortality rates per million population in 117 countries with 150 or more COVID-19 cases.

Data was accumulated on each country, examining people aged 65 and over, incorporating data on population density and air pollution, while latitude was entered for each country’s capital city. Researchers tested their hypothesis that there was no link between mortality and latitude below a defined threshold, and that thereafter mortality increased with latitude.

• The association between COVID-19 mortality and latitude exists above 28 degrees, not far from the latitude (35 degrees) beyond which populations often have insufficient ultraviolet B exposure, to maintain normal vitamin D blood levels through winter and spring.Cognitive performance was not worse in older people with low vitamin B12 combined with high folate (representing 1.5pc of older adults in Ireland).

What does the research show?

• The study identifies how age adjustment played a significant factor in rising mortality rates, with an estimated increase of 13% in mortality for each 1% increase in the proportion of people aged 65 and over.

• Latitude remains significant after adjustment for age with an estimated 5% increase in death rates for each degree further north the country was located above a threshold of 28 degrees north.

• Countries with higher pollution included many with younger populations, and pollution was negatively associated with mortality but did not add significantly to a model containing latitude and age.

• Population density per country was not significantly linked with mortality.

Key Findings • The study has found that the proportion of older people in each country greatly affected COVID-19 mortality rates, but after adjustment for this, a strong association remains across the Northern hemisphere between more northerly latitude and higher death rates from COVID-19.

It is widely documented that Vitamin D offers many positive benefits to overall health; including boosting the body’s immune response, supporting bone and muscle health and in playing a potentially critical role in suppression of the severe proinflammatory response.

Evidence linking vitamin D deficiency with COVID-19 severity is circumstantial but growing.

The researchers point out that if the association between vitamin D deficiency and COVID-19 severity is causative, the disease should prove seasonal, since more severely affected individuals are infectious for longer. The researchers recommend supplementation of 800-1000 International Units (20 -25 micrograms) daily to ensure normal blood values, especially for those at greater risk of deficiency, such as people with darker skin or living in institutions.

Professor Rose Anne Kenny, Principal Investigator of TILDA and author of the study said, “Our group is cautious about ascribing a causal association in advance of results from Vitamin D supplementation studies which are on-going. However, given the high prevalence of Vitamin D deficiency in many northern latitude countries, the reduction in outdoor physical activity during COVID, and the safety of Vitamin D, public health bodies in Ireland and UK are

"It is plausible that vitamin D deficiency increases risk of severe COVID-19 illness, but all the evidence is indirect.

The correlation between COVID-19 mortality and northern latitude, with consequently reduced ultraviolet exposure from sunlight, adds to this evidence.” recommending that older persons, those who are mainly indoors and those from other high risk groups such as BAME, should take regular supplements.”

Professor Jon Rhodes, Emeritus Professor of Medicine, University of Liverpool and co-author of the study added, “Vitamin D is an unusual vitamin – it is a hormone and we get most of it by the action of ultraviolet light on cholesterol in the skin. Unless you live in a sunny

country or eat a very large amount of oily fish you are quite likely to need supplements to maintain a normal level. It is plausible that vitamin D deficiency increases risk of severe COVID-19 illness, but all the evidence is indirect. The correlation between COVID-19 mortality and northern latitude, with consequently reduced ultraviolet exposure from sunlight, adds to this evidence.”

HOSPITALPROFESSIONALNEWS.IE | HPN • JUNE/JULY 2020

10 Research

Asthma rates in the Over-50s Asthma rates higher among over-50s living in areas with more local air pollution Originally published by ESRI. Dr Anne Nolan, Associate Research Professor in the Social Research Division, and joint Research Area Coordinator for Health and Quality of Life Research at the ESRI

income and history of smoking.

Two methods of identifying those with asthma were used, giving similar results: participants were asked if they had ever had a diagnosis of asthma and the study checked if they were using any asthma medications (such as inhalers).

Asthma affects over 300 million people worldwide, and is the world's most common chronic respiratory condition. New collaborative research sheds insight highlighting how older adults who live in areas with higher levels of air pollution are more likely to have asthma.

Researchers have published a study showing that over-50s in Ireland living in areas with higher levels of air pollution are more likely to have asthma. The study, published in the International Journal of Epidemiology, was carried out by a team from ESRI, TCD, RCSI, TU Dublin and IT

Carlow. The study linked health data from 8,162 participants in The Irish Longitudinal Study on Ageing (TILDA) to estimates of annual average nitrogen dioxide (NO2) concentrations near their homes.

NO2 is an air pollutant associated mainly with road transport sources such as cars, trucks and buses. Those living in areas with higher NO2 concentrations had significantly higher rates of asthma.

The researchers carried out a statistical analysis of the data, controlling for many personal characteristics that might affect asthma risk, such as age, sex,

Overall, 9% of the sample aged 50+ reported an asthma diagnosis, and 6.9% reported using relevant medications (such as inhalers). Living in an area with higher NO2 concentrations was found to be associated with an increased probability of asthma.

For example, a 1 part per billion (ppb) increase in local NO2 was associated with a 0.24 percentage point increase in the probability of reporting an asthma diagnosis, and the effect size was similar for the probability of using asthma medication (0.21 percentage points). To put these results in context, the average

exposure to NO2 in this sample was 4.8ppb, with 95 per cent of the sample exposed to NO2 levels below 13 ppb.

Asthma affects over 300 million people worldwide, making it the most common chronic respiratory condition. Previous research on asthma and air pollution has focused on the risk to children.

There has been less evidence of possible risks to older people.

More research will be needed to show if air pollution causes asthma or makes it more severe for older groups, but these results are suggestive that there might be such links.

One of the team, Professor Margaret O’Mahony from TCD, said, “The results demonstrate the importance of research on the health impacts of air pollution and we would recommend more investment in both health and air pollution data collection to improve our knowledge of these effects.”

Dr Anne Nolan from ESRI added, “Ireland has good air quality compared to many other countries, but the study found higher levels of asthma among people exposed to even relatively small increases in NO2.”

The Irish Longitudinal Study on Ageing (TILDA), Trinity College Dublin, is a nationally representative study of people age 50 and over in Ireland. TILDA is funded by the Department of Health, Science Foundation Ireland, The Atlantic Philanthropies and Irish Life.

Update on Plans for Ending FMD Use and Learn in Ireland The Safety Features Oversight Group has been reviewing plans to end the FMD use and learn period on a phased basis in light of the COVID-19 pandemic. The Group recognises that this crisis has placed considerable strain on all parties involved in the medicines supply chain in Ireland – pharmacies, hospitals and wholesalers as well as manufacturers, MAHs and parallel importers/distributors – and acknowledges the excellent work being done by everyone to maintain the supply of medicines, while ensuring staff and public safety. The obligation to move towards full compliance with the Falsified Medicines Directive (FMD) remains, however, given the unique circumstances in which we find ourselves, it has been decided to delay plans previously notified to end the use and learn period for wholesalers in May and for pharmacies and hospitals in September.

The Safety Features Oversight Group will continue to closely monitor the situation over the next few weeks and new dates for ending the use and learn period will be notified in due course. In the meantime, the advice is as follows: 1. If you have any queries about your FMD obligations, please contact the PSI (Retail Pharmacy Businesses), HSE FMD project team (public hospitals), HPRA (wholesalers, MAHs, manufacturers, parallel importers, parallel distributors).

2. Parallel importers and parallel distributors should continue to comply with the guidance issued to them by the HPRA on 7th February.

3. Please contact IMVO if you have queries about your connection to the national system (including new registrations, login queries, change of FMD software provider) or want to follow up on specific alerts or scanning issues.

4. If at any stage you have grounds for believing that a pack has been interfered with or could be falsified, please report this to the HPRA, by email to qualitydefects@hpra.ie or using the HPRA’s online reporting system https://www.hpra.ie/homepage/about-us/report-an-issue (select the link called ‘Report an issue’, then ‘Medicine Quality Issue/Defect’).

JUNE/JULY 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

Coronavirus Library

FONDAZIONE INTERNAZIONALE MENARINI www.fondazione-menarini.it/ Home/Coronavirus-Library

The Virus

Pathophysiology

Epidemiology and Responses to the current emergency

Coronavirus (Covid-19) Immunology

The Coronavirus (COVID-19) is a highly contagious and virulent virus that has changed our lives completely in a very small period of time.

Clinical Aspects

An Invitation to Learn More

Treatment

Trials

Institutional Recommendations

In appreciation of all health care professionals working under the unprecedented challenges presented by the COVID-19 pandemic, Fondazione Internazionale Menarini has developed a Coronavirus Library, offering free access to up-to-date medical content from renowned journals.

Through its association with Fondazione Internazionale Menarini and as part of its ongoing commitment to Continuous Medical Education, A.Menarini Ireland invites you to access this library to gain further expertdriven knowledge in the fight against COVID-19.

A.Menarini Pharmaceuticals Ireland Limited, Castlecourt, Monkstown Farm, Monkstown, Glenageary, Co. Dublin.

For more information please visit www.menarini.ie DISCLAIMER STATEMENT: A.Menarini is inviting healthcare professionals to access the Menarini Foundazione International coronavirus library as an information resource the website is controlled by Menarini Foundazione International and is not under the control of A.Menarini Pharmaceuticals Ireland Ltd. The selected links contained on the website offer access to third party websites, which are beyond the control of Fondazione Internazionale Menarini. Consequently, Fondazione Internazionale Menarini cannot be held in any manner liable either for the contents of such websites (including, by way of example but not limited to, the links contained within them), or for the amendments and/or updates of the same. The access and use of third party websites is at the visitor’s own risk and it is subject to their respective website’s terms of use.

IR-MEN-23-2020. Date of Item: April 2020

FONDAZIONE INTERNAZIONALE MENARINI

12 Covid-19

Life and work as we know it has changed, and changed utterly

Written by Dr Diarmuid O'Shea, Registrar, RCPI

Dr Diarmuid O'Shea, Registrar, Royal College of Physicians Ireland

clinical updates online to hundreds of doctors, allowing them to keep up to date with this new and rapidly evolving area of clinical practice. We know everything is not COVID-19 related, so you will see our masterclass webinar series evolve over the coming months.

The lifting of restrictions in Ireland has begun and we are slowly returning to a “new normal”. I am sure, like me, you find it difficult to put into words the experiences we have had over the past eight weeks. Life and work as we know it has changed, and changed utterly. Now we collectively hold our breath to see what happens over the next few weeks - watching test results, hospital admissions, ICU admissions, the numbers dying, and will “the curve” stay flat.

I watched with admiration as colleagues, doctors, nurses, allied health professionals, support staff and management teams right across the community and hospital sector came together to meet extraordinary challenges in a very short space of time.

Each of us is having a uniquely individual experience of the pandemic While our collective experiences have much in common, each of us is also having a uniquely individual experience of this pandemic. Now is also a time for each of us to stop, pause and reflect. Even if you are not the type of person to keep a diary, I would encourage you to

write a short account of your own story of work and life in the early stages of these COVID-19 times.

Look on it as a ‘message in a bottle’ - capture it and seal it.

In case you are not aware, the RCPI Heritage Centre is seeking to capture healthcare workers’ experiences on the pandemic and is inviting you to submit an account of your experiences to the archive to, as a record of your unique experience, and to aid future research.

Adapting to change Behind the scenes, away from the frontline, RCPI has been adapting at a pace that matches everything you have seen happen in the workplace. We have lots to do and are very busy on your behalf. The dedicated College staff and team led by our President, the CEO, College Officers, Executive Board and Council, continues to work together to drive changes that will enable you to meet your training, educational and professional competence needs in a profoundly changed healthcare landscape.

One highly visible example of how we are adapting to the crisis is our masterclass webinar series on Covid-19. We broadcast these

JUNE/JULY 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

In July 2020 the planned changeover of BST and HST take place, admittedly in changing times. For the first time, this year’s Interns will start early, coming straight out of university, following early exams and virtual graduations. They will be a welcome early addition as they embark on their medical careers in truly unusual times. There is uncertainty about what is to happen in the year ahead. Doctors who answered Ireland’s call and returned to work in the Irish health service, as well as those who were planning to go abroad, will be looking for employment opportunities at a time when we badly need more doctors. We are working closely with the HSE to explore how best to achieve and support these doctors when appointed. Further updates on this will follow.

Those that step into new BST and HST roles will also need additional support. Work and training as we know it is has changed and we need to figure out how best to support, record, and acknowledge this. What is absolutely certain is that the experience we have all had since March this year is one that no curriculum could have set out. So each of us, whether we are practicing doctors, Trainees, Members or Fellows must find a creative way of capturing the learning from these experiences.

The emotional impact on this pandemic on us and the importance of self-care I have always been very proud of where I work and the people I work with. Of late, I have watched with admiration and pride the commitment and dedication of the teams I work with. I have watched people, understanding the risks, selflessly come to work, day in, day out. I have watched doctors, young and not so young, flexibly and without a second thought cover shift after shift. They have done this with a good humour and collegiality that makes me proud of the profession I am in and the training that RCPI provides.

I have also watched as we have become tired by the relentless pace and demand on us all, as colleagues we work with anxiously await swab results or become ill, as we worry about what is happening to family and friends outside the workplace. I have watched as people grieve for lost family and friends. While we have spent lot of time focusing on others, we must also focus on ourselves and each other in the workplace.

We need to remain very aware of the importance of self-care, now more than ever. We spend most of our waking minutes thinking of others, but I urge you to give yourself time to reflect on how truly momentous and difficult the last few months have been. If you do not take care of yourself through all of this, you cannot effectively help and support others. So please take time for yourself. Acknowledge the work you have done, the contribution you have made to this moment in history, and know, as this pandemic passes, and it will pass, the support and care you delivered to your patients made a real difference in their lives.

Don’t be afraid or embarrassed to talk to a friend or a mentor.

And remember that a few wellplaced words of appreciation or encouragement to colleagues cost little, but can make a real difference in someone’s day.

Thank you for all you are currently doing in your workplaces. It is at times draining and exhausting, but together we are stronger. You are doing the College, our profession and our country proud.

News 13

Psychiatrist Survey shows Referral increase As coronavirus restrictions begin to ease, a survey of Consultant Psychiatrists carried out by the College of Psychiatrists of Ireland shows the emergence of a new mental health curve that will need flattening. With a worrying increase in referrals, urgent and acute presentations to specialist mental health services and relapses, a previously predicted surge in mental illness presentations looks increasingly likely.

Almost 200 College member consultant psychiatrists (N=195) responded to its ‘Covid-19 Impact on Mental Health Services’ survey from across Ireland, the majority of which were (84%) from community healthcare services (HSE CHO Community Health Organisations).

(The College survey was sent to 623 consultant psychiatrists and achieved a 31% response rate).

As expected, 68% of respondents

saw an initial lull in referrals to mental health service following the “lockdown” on 27th March with a subsequent increase in the second month of lockdown (April 24th to May 22nd).

Strikingly, when compared with numbers prior to the lockdown, 1 in 3 consultant psychiatrists (35%, N=48) saw an increase in the number of emergency referrals and 50% cited the number of patients experiencing a relapse of mental illness as having increased (N=66).

Other key findings: • 59% of respondents also felt that demand for inpatient beds had increased in the past month compared to the first month of the lockdown.

• The number of new referrals to secondary mental health services in the past month had increased or significantly

increased according to 72% of consultant psychiatrists compared to the first month of lockdown with 35% believing the number of referrals had increased compared to from before the lockdown.

• Approximately 80% of consultants felt that social isolation and reduced access to face to face secondary mental health supports was contributing to emergency presentations.

• Additional factors such as reduced access to local counselling supports and general practitioners, abuse/neglect in the home environment and increased reliance on drugs/alcohol were also believed to be contributing to emergency presentations.

The impact of school closure was also highlighted as a significant stressor.

• A swell in presentations across the range of mental disorders in the past month compared to the first month of the lockdown are reported such as: 64% saw increase in self-harm/suicidal ideation*; 57% in new onset depression; 79% in generalised anxiety with many reporting increased complexity in presentations across this range.

Commenting Dr William Flannery, President said, “Although a longer period to gather more data is needed as predicted an increase in presentations and incoming pressure on the mental health services is clearly arising, and concerns about the impact of this an already overburdened, underdeveloped Mental Health Service in Ireland are chief amongst Consultant Psychiatrists and their teams.”

Pfizer ‘Keep the Beat’ Atrial fibrillation in Ireland is the commonest rhythm disorder affecting the heart. Around 5% of people over the age of 60 have it. Around 10% over the age of 75 have atrial fibrillation. As populations age, we will see an increase in the numbers of AF cases.

Atrial fibrillation is an irregular and often rapid heart rate that can increase the risk of strokes, heart failure and other heartrelated complications.

Pfizer Healthcare Ireland launched the Keep The Beat awareness campaign in February 2019. After six months of planning the videoled campaign went live across all

social media channels, on flagship RTÉ Radio shows and local stations across the country as well as print adverts in February 2019.

The overall objective of the Keep The Beat campaign was to raise awareness for Atrial Fibrillation (AFib), a heart rhythm disorder that is more common as people get older. AFib is a type of arrhythmia – when your heart starts beating out of rhythm, sometimes quite fast. When this happens the upper chambers of the heart (the Atria) do not pump in the normal way which may cause blood to pool and clot.

A part of the clot may break off and travel in the bloodstream to the brain, where it lodges, causing a stroke.

The campaign aimed to deliver a very serious message in an informative yet entertaining way, we wanted people who watched the video or heard the ad to find out more about AFib and also wanted to ensure the message conveyed was memorable.

This multi-channel campaign builds

on Pfizer’s work with the Irish Heart Foundation including our support of their Feel The Pulse initiative which launched in November 2018.

There were three key call to actions for this Keep The Beat campaign; to check out www.keepthebeat.ie, talk to your doctor and download the AF booklet online.

Integrating Pharmacists to Optimise Care Research undertaken by RCSI University of Medicine and Health Sciences suggests that integrating pharmacists into general practice teams facilitates collaboration to optimise treatment plans for patients with long-term medical needs and alleviate pressures on GP practices.

The study, conducted by researchers in RCSI’s Department of General Practice and School of Pharmacy and Biomolecular Sciences, is published in BMJ Open.

Researchers selected four GP practices with approximately 35,000 patients to participate in the study over a six-month period.

During this time, pharmacists were integrated into and worked in these practices reviewing prescriptions to support existing GP teams. They flagged 786 patients who had 1,521 potential issues relating to medication effectiveness or concerns over possible side effects. The most common medications involved were proton pump inhibitors

used to suppress stomach acid, benzodiazepines used to treat anxiety or insomnia and antiinflammatory drugs.

Over 50% of these issues resulted in a change being made by the patient’s GP, such as reducing the dose or ending a prescription where the risks outweighed the benefits or the medication was no longer necessary. Overall, the changes to prescriptions in the four GP practices amounted to potential cost savings of approximately ¤57,000 each year.

“Our findings clearly demonstrate the possible benefit of introducing general practice pharmacists to the Irish healthcare system. While further study is needed to establish the cost-effectiveness of such an initiative nationwide, implementing it would work towards alleviating the pressure our GPs are under and improving the quality of care for Irish patients,” said senior author Dr Frank Moriarty, a pharmacist and lecturer at the School of Pharmacy and Biomolecular Sciences.

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14 News

Doctor difficulty in securing jobs Professor Áine Carroll, Dr Cara McDonagh, Ricky Healy and Professor Mark Delargy The Irish Medical Organisation (IMO) has called on the Government to ensure that no doctor is left without a placement either during or after the Covid-19 pandemic, after an IMO survey of NCHDs (Non Consultant Hospital Doctors) emphasised the difficulty that some Doctors, particularly incoming senior house officers (SHOs), are having in securing a job.

Three-quarters (74%) of respondents who said they were having difficulty securing a job are incoming SHOs who are due to take up a post in July.

Dr Paddy Hillery, Chair of the NCHD Committee of the IMO, said that this was an opportunity for the Government to enhance our medical workforce after years of substandard resourcing. “We are currently faced with lengthy waiting lists, far too few doctors in our health system and a potential second surge of Covid-19. The Government must firstly offer temporary consultant

locum posts to all doctors who have finished training, and also ensure that no other NCHD is left without a placement to continue their training.

“With such an extreme shortage of doctors across the full spectrum of the health system, it is frankly unbelievable that the Government and Health Service Executive (HSE) would allow any doctor to slip through the cracks when our healthcare needs are so acute.”

Dr Hillery said that this offer would also help existing NCHDs who are physically and mentally exhausted in light of Covid-19.

“Doctors across all specialties have answered the country’s call during the Covid-19 pandemic, in many cases to the detriment of their own health as they worked particularly excessive hours for the past three months. A key part of dealing with a potential second surge of Covid-19 is retaining our existing staff and attracting additional staff so that we can build a resilient workforce.

“Ultimately, this is about patients benefiting from quality care, which will not happen if junior doctors are left in limbo, unable to work and made unemployed.”

New National Rehabilitation Hospital opens New National Rehabilitation Hospital

facilities will make a real difference to the lives of the children and adults who pass through the doors of the NRH.”

The Board of the National Rehabilitation Hospital have announced that all patients have now moved into Phase One of the long-awaited new rehabilitation hospital.

Minister Simon Harris commented, “Three years ago, the Taoiseach and I turned the sod on this new facility and today the transition is complete.

“I want to congratulate all who worked so hard to make this a reality. This new development will enable staff to deliver optimal quality care and treatment in a facility which affords dignity, respect and privacy to all. It will be a major enhancement to rehabilitation services in the country and will have a direct and significant impact on patient recovery. These new

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Professor Mark Delargy, NRH Clinical Director added, “After so many years waiting for investment in rehabilitation, the new hospital far exceeds expectations. Each patient now has an en-suite single room designed for their comfort and rehabilitation needs. For years we had to fit our patient services into a suboptimal environment. Our old, overcrowded, and cramped Nightingale wards hold many memories for our patients, and these we will keep, but we have gladly left those wards behind.

Staff are enjoying seeing their patients explore the new facilities and take in the unparalleled views

over the Dublin Mountains. Each of our treatment units set new standards for bespoke adult and Paediatric rehabilitation.”

Phase one of the three-phase major Capital Development is a partnership between the HSE and the NRH. The development is purpose built with 120 single ensuite rooms, integrated therapy services, hydrotherapy pool and sports facilities, all of which are specifically designed to accommodate the needs of those requiring complex specialist rehabilitation services. The design is patient-centred and based on the principles of empowerment, dignity, privacy, confidentiality and choice. The first design of its kind in Ireland, the new hospital complies with best international practice and infection prevention and control guidelines – a vital requirement in minimising the potential for transmission of COVID-19, and to facilitate more effective management of Health Care Acquired Infections (HCAIs).

For COPD patients on treatment with ICS/LABA and at risk of exacerbation*1 *A worsening of symptoms or a history of exacerbation treated with antibiotics or oral corticosteroids in the past 12 months

It’s the things you do today that make a big difference 1-3 to their tomorrows TRELEGY Ellipta provides your patients with statistically superior improvements in lung function and health-related quality of life, and reduction in annualised rate of moderate/ severe exacerbations** vs. budesonide/formoterol***1–3 Fictional patient, for illustrative purposes only

Start your patients on TRELEGY Ellipta today, expect more from tomorrow 1,2

**Moderate exacerbation is a worsening of symptoms or a history of exacerbation treated with antibiotics or oral corticosteroids. A severe exacerbation is a worsening in symptoms that required hospitalisation.

TRELEGY Ellipta (FF/UMEC/VI) 92/55/22 mcg OD is indicated for maintenance treatment in adult patients with moderate to severe COPD who are not adequately treated by a combination of an ICS and a LABA or a combination of a LAMA and a LABA1

Today. Tomorrow. TRELEGY. 2-3

▼This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. ***Co-primary endpoints were change from baseline in trough FEV1 and SGRQ at week 24 (n=1810). A subset of patients (n=430) remained on blinded study treatment for 52 weeks. Trelegy showed an improvement in trough FEV1 of 171mL versus budesonide/formoterol (p < 0.001, 95% CI 148,194) at week 24. Trelegy showed an improvement in health-related quality of life (SGRQ) of 2.2 units (p <0.001, 95% CI 3.5, 1.0) at week 24. At week 52 in a subset of patients Trelegy showed a 44% reduction in annualised rate of moderate/severe exacerbations versus budesonide/formoterol (95% CI 15,63, p=0.006, Absolute difference 0.16).

TRELEGY Ellipta is generally well tolerated. Common adverse reactions include: pneumonia, upper respiratory tract infection, bronchitis, pharyngitis, rhinitis, sinusitis, influenza, nasopharyngitis, candidiasis of mouth and throat, urinary tract infection, headache, cough, oropharyngeal pain, constipation, arthralgia, back pain1 FF, fluticasone furoate; ICS, inhaled corticosteroid; LABA, long-acting ß2-agonist; LAMA, long-acting muscarinic antagonist; OD, once-daily; UMEC, umeclidinium, VI, vilanterol References: 1. TRELEGY Ellipta SmPC 2019. 2. Lipson DA et al. Am J Respir Crit Care Med 2017; 196:438–446. 3. Lipson DA et al.N Engl J Med 2018; 378:1671–1680.

Trelegy▼ Ellipta (fluticasone furoate/umeclidinium/vilanterol [as trifenatate]) Prescribing information.

Please consult the full Summary of Product Characteristics (SmPC) before prescribing. Trelegy Ellipta (fluticasone furoate/umeclidinium/vilanterol [as trifenatate]) inhalation powder. Each single inhalation of fluticasone furoate (FF) 100 micrograms (mcg), umeclidinium bromide (UMEC) 62.5 micrograms and vilanterol as trifenatate (VI) 25 mcg provides a delivered dose of 92 mcg FF, 55 mcg UMEC and 22 mcg VI. Indications: Maintenance treatment in adult patients with moderate to severe COPD who are not adequately treated by a combination of an inhaled corticosteroid (ICS) and a long-acting ß2-agonist (LABA) or a combination of a LABA and a long acting muscarinic antagonist. Dosage and administration: One inhalation once daily at the same time each day. Contraindications: Hypersensitivity to the active substances or to any of the excipients (lactose monohydrate & magnesium stearate). Precautions: Paradoxical bronchospasm, unstable or life-threatening cardiovascular disease or heart rhythm abnormalities, convulsive disorders or thyrotoxicosis, pulmonary tuberculosis or patients with chronic or untreated infections, narrow-angle glaucoma, urinary retention, hypokalaemia, patients predisposed to low levels of serum potassium, diabetes mellitus. In patients with moderate to severe hepatic impairment patients should be monitored for systemic corticosteroid-related adverse reactions. Eye symptoms such as blurred vision may be due to underlying serious conditions such as cataract, glaucoma or central serous chorioretinopathy (CSCR); consider referral to ophthalmologist. Increased incidence of pneumonia has been observed in patients with COPD receiving inhaled corticosteroids. Risk factors for pneumonia include: current smokers, old age, patients with a history of prior pneumonia, patients with a low body mass index and severe COPD. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take Trelegy. Acute symptoms: Not for acute symptoms, use short-acting inhaled bronchodilator. Warn patients to seek medical advice if short-acting inhaled bronchodilator use increases. Therapy should not be abruptly stopped without physician supervision due to risk of symptom recurrence. Systemic effects: Systemic effects of ICSs may occur, particularly at high doses for long periods, but much less likely than with oral corticosteroids.

Interactions with other medicinal products: Caution should be exercised with concurrent use of ß-blockers. Caution is advised when co-administering with strong CYP3A4 inhibitors (e.g. ketoconazole, ritonavir, cobicistat-containing products), hypokalaemic treatments or non-potassium-sparing diuretics. Co-administration with other long-acting muscarinic antagonists or long acting ß2-adrenergic agonists is not recommended. Pregnancy and breast-feeding: Experience limited. Balance risks against benefits. Side effects: Common (≥1/100 to <1/10): pneumonia, upper respiratory tract infection, bronchitis, pharyngitis, rhinitis, sinusitis, influenza, nasopharyngitis, candidiasis of mouth and throat, urinary tract infection, headache, cough, oropharyngeal pain, arthralgia, back pain. Uncommon (≥1/1,000 to

Find out more here:

www.trelegy.ie or request a visit from a GSK representative

<1/100): viral respiratory tract infection, supraventricular tachyarrhythmia, tachycardia, atrial fibrillation, dysphonia, dry mouth, fractures; Not known (cannot be estimated from the available data): vision blurred. Marketing Authorisation (MA) Holder: GlaxoSmithKline Trading Services Limited, Curabinny, Co. Cork, Ireland.

MA No. [EU/1/17/1236/002]. Legal category: POM B. Last date of revision: June 2019. Code: PI-2093. Further information available on request from GlaxoSmithKline, 12 Riverwalk, Citywest Business Campus, Dublin 24. Tel: 01-4955000.

A full list of adverse reactions for TRELEGY Ellipta can be found in the Summary of Product Characteristics.

Adverse events should be reported to the Health Products Regulatory Authority (HPRA) using an Adverse Reaction Report Form obtained either from the HPRA or electronically via the website at www.hpra.ie. Adverse reactions can also be reported to the HPRA by calling: (01) 6764971.

Adverse events should also be reported to GlaxoSmithKline on 1800 244 255.

TRELEGY Ellipta was developed in collaboration with ©2020 GSK Group of Companies or its licensor Trademarks are owned by or licensed to the GSK Group of Companies PM-IE-FVU-ADVT-200002 | February 2020

16 News

Virtual Outpatients at Mayo Professor Paul O’Grady, Consultant Orthopaedic Surgeon, Mayo University Hospital In response to the COVID outbreak, the Orthopaedic and Physiotherapy teams at Mayo University Hospital (MUH) developed virtual clinics to assess patients with fractures who could be managed remotely. With the support of hospital management and co-operation from Radiology, Administration and Nursing staff, the special clinics have minimised hospital visits for hundreds of patients, keeping them safe at home as much as possible Commenting Professor Paul O’Grady, Consultant Orthopaedic Surgeon at Mayo University Hospital said, “Despite the significant impact COVID-19 had on the health services over the last number of months, people are still sustaining injuries, including fractures and need to be treated and followed-up. Our emergency orthopaedic service has continued and we have seen

Sarah Dunne, Physiotherapist, Mayo University Hospital

many patients in our clinics. As we now move to restoring more of our clinics, including our followup clinics, we have started to use technology to support our clinic.

This is particularly important for vulnerable or older patients and it allows us assess them remotely and avoids the need for them to attend the hospital.

The technology we have put in place allows us view patients x-rays or CT scans remotely and then we can determine the most appropriate treatment for patients.

This system also allows us speak with our patients and almost 70% of the outpatient consultations in our fracture clinic are being done remotely. When it is necessary or clinically appropriate, patients attend the clinic in person. The feedback from our patients has been really positive to date.”

In relation to the use of virtual clinics for patients of the Physiotherapy Department, Sarah Dunne, Physiotherapist said, “Over the last few months our department has been providing patients with a telehealth service.

Through the use of an app we have been able to offer our patients phone and video call consultations. During these consultations we are able to

accurately assess our patients, address any queries and concerns they may have, provide them with advice and implement suitable treatment plans. Telehealth has proven to be a really effective means of treatment for patients of all ages. It has allowed us to provide our patients with ongoing support and continuity of care, which has been especially welcomed by patients who are cocooning.”

Catherine Donohoe, Hospital Manager Mayo University Hospital added, “Across the hospital we are looking at different ways of using technology so we can further increase access and improve the care we provide to our patients.

While there are a proportion of outpatient clinics or appointments that need to continue face to face, many can be done remotely which means the patient does not have to travel to the hospital. Over the coming months as we work to manage implementing social distancing across our services, being able to run virtual clinics or use telemedicine will be even more important. I am very grateful to the team in MUH for the effort they have put in to progress telemedicine and I am excited about expanding this in the future.”

Investment in COVID-19 Research Project Provost Patrick Prendergast, Professor Aideen Long, Professor Luke O’Neill, Minister Simon Harris, Professor Kingston Mills, AIB CEO Colin Hunt, pictured in TBSI’s Immunology Lab

AIB COVID-19 Research Hub in Trinity to urgently accelerate the college’s immunology project tackling the COVID-19 pandemic.

Trinity College Dublin has welcomed the Government’s ¤4.8M investment into a collaborative partnership at the university researching the immune response to COVID-19.

The investment is being made

by Government through Science Foundation Ireland with further funding from the private sector. In April, AIB committed ¤2.4 million to back the establishment of the

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The collaboration brings together a strong multi- and inter-disciplinary approach, combining the leading expertise of Trinity College Dublin, with other national and international collaborators. The partnership is led by Prof Kingston Mills and Prof Aideen Long at the Trinity Biomedical Sciences

Institute (TBSI) and Trinity Translational Medicine Institute (TTMI), Trinity College Dublin.

The research will seek to understand why some people are more susceptible to Covid-19 than others. The immunologists will develop, validate and deploy rapid anti-SARS-CoV-2 antibody testing in Ireland to identify previous SARS-CoV-2 infection in high priority healthcare workers and in the general community.

News 17

Accelerating development of new vaccine Dr Mark Barrett, CEO, APC

APC, the award-winning Irish research and development company that partners with the global pharmaceutical and biotech industry to accelerate the development and launch of quality, life-changing medicines to patients, has announced a partnership with Vaxine Pty Ltd, an Australian biotechnology company, to accelerate the development and launch of a vaccine candidate against the SARS-CoV-2 coronavirus (COVID-19).

Established in 2011 by Dr Mark Barrett (CEO) and Professor Brian Glennon (CTO), APC utilises its proprietary state-of-the-art technology platforms and globally recognised research team to expedite how drug manufacturing processes are researched and developed. In addition to the Covid-19 vaccine candidate, APC is currently working on 20+ medicines for a variety of cancers, respiratory diseases, Alzheimer’s disease and HIV at its 60,000 sq. ft. HQ in Dublin.

APC currently employs a team of 130 people, the majority of which are chemical engineers, process and biopharmaceutical scientists. The company is the one of the largest employers in Ireland of scientists and PhD qualified chemical engineers.

Commenting on this new partnership, APC Chief Executive Officer Dr Mark Barrett said, “Never before has the combination of novel vaccine and processing sciences been so important to the world. ‘Time-to-patient’ needs considerable disruption, with both

clinical and CMC manufacturing science needing to be challenged.

“Today through this strategic partnership APC and Vaxine signify our collective intent to combine the latest innovation in COVID-19 vaccine technology, and processing sciences, BioACHIEVE ™, to accelerate the development and launch of Vaxine’s novel COVAX-19™ vaccine.

“Vaxine and APC share a cultural commitment to innovation, dynamism, and a focus on reducing disease burden through innovative science and development. It is an honour and a privilege for APC to be part of the world’s focus on solving this ‘time-to-patient’ for a COVID-19 vaccine. Through collaboration and partnership, I am confident

APC can play a leading role in dramatically accelerating the timeframe for Vaxine’s COVAX-19™ vaccine to be made globally available.”

Vaxine have a stellar track record in developing novel vaccines for pandemic influenza, hepatitis B, Japanese encephalitis, RSV, Ebola, and HIV, amongst many others. Vaxine’s Chairman and Research Director Nikolai Petrovsky commented, “APC brings outstanding process development and manufacturing science capabilities through their BioACHIEVE ™ platforms and best in-class team of scientist and engineers, making them an ideal partner to enable our COVAX-19™ to be accelerated to patients and to the market.

Vaxine’s novel technology which

combines recombinant proteins with an innovative Advax-SM adjuvant, which acts as an immune turbocharger, ensures a highly potent and durable protective immune response against COVID-19.”

Professor Petrovsky commented further, “Following completion of clinical trials, which are currently being initiated, Vaxine wishes to make its COVAX-19™ vaccine available to as many countries of the world as possible. There is an extraordinary unmet demand for effective and safe COVID-19 vaccines. By partnering with professional process development companies such as APC, who can assist with large scale process and technology design, optimisation and technology transfer, will assist us in meeting such demand.”

Updates on bowel cancer test More than 2,700 people are waiting for an urgent bowel cancer test the latest figures show, with Covid-19 piling additional pressure on an already under-resourced service. The Irish Cancer Society is calling for urgent action to ensure that people are not left waiting for this important cancer test, which could lead to a delayed diagnosis.

Dr Anthony O’Connor, a Consultant Gastroenterologist, said, “People who require an urgent colonoscopy should be seen in 28 days under best practice. This is not happening for too many people and many more people will be left waiting for far too long unless we see steps taken now. The longer people have to wait the greater risk we are taking

with their outcome if they are found to have cancer.

“The entire health system is playing catch up due to covid-19 but endoscopy was already behind – this is why we need to see investment including the recruitment of more triage nurses and the expansion of non-invasive testing, including FIT and Calprotectin for appropriate patients.”

CEO of the Society, Averil Power, said, “It is unrealistic and utterly unacceptable to expect that endoscopy services can catch up with this urgent demand with their current funding, staffing and resources, especially at a time when units will be operating at a reduced capacity in order to meet public health guidelines.”

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18 Respiratory

Lung health set to become one of the biggest casualties of COVID-19

Dr Aidan O'Brien, Irish Thoracic Society

“It is clear that we are storing up a backlog of undiagnosed and untreated respiratory disease at a magnitude that will have untold implications for the healthcare service and for our patients in the coming months and years unless urgent action is taken.”

These were the words of Dr Aidan O'Brien, President of the Irish Thoracic Society recently.

Leading respiratory experts from the Irish Thoracic Society have warned of the impact of COVID-19 on lung health and called for urgent action to avert unprecedented rates of excess illness and death from lung disease. According to the Society, additional resources for the diagnosis, treatment and ongoing care of people with respiratory conditions are crucial if we are to prevent a lung disease crisis.

This is due to the potential longterm health impacts for some of those who have recovered from the acute stage of COVID-19, as well as those who are already living with a respiratory condition but who have not been able to access timely treatment and care, and who are also in the more vulnerable patient category should they contract COVID-19.

The respiratory experts on the Society's COVID-19 sub-group, who include representatives from all hospital groups and disciplines, have expressed disappointment that the Programme for Government Our Shared Future does not include a targeted response to the burden

"We commend the Herculean efforts of our colleagues throughout the healthcare system in retaining access to non-COVID-19 healthcare as much as possible while addressing the specific challenge of COVID-19 through separate access streams, virtual consultations and other innovative solutions" on respiratory healthcare services amidst fears that lung health is set to become one of the biggest casualties of COVID-19.

Specifically, they are calling for greater numbers of respiratory specialists and other healthcare professionals to provide essential care in community as well as hospital settings, investment in infrastructure to ensure necessary space and isolation facilities, and the development and provision of cutting-edge technology solutions for patient care.

Triple-Threat According to the Society, as Ireland enters an indefinite period of reduced access to healthcare services due to necessary physical distancing and infection control at the country's healthcare facilities, COVID-19 has inflicted a triple-threat impact on lung health: • COVID-19 is itself a respiratory illness that has dramatically

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and unexpectedly increased the already significant burden of respiratory disease both in terms of short-term acute illness and potential long-term damage to the lungs which will require ongoing monitoring and care for some patients; • People with existing respiratory diseases are particularly vulnerable to complications if they contract COVID-19; and • People with new and existing respiratory diseases face delayed access to essential care due to COVID-19 restrictions – this comes on the heels of a ten-week hiatus for acute respiratory admissions and routine respiratory care.

Before COVID-19 ever happened, Ireland's lung disease rates were already amongst the highest in the world and the numbers of respiratory specialists per capita amongst the lowest.

In 2016, respiratory disease was the cause of one in five deaths in Ireland, and Ireland's death rate from respiratory disease was the fourth highest in the EU-28 and 38% higher than the EU average. In 2016, respiratory disease accounted for more hospitalisations than for cardiovascular and non-lung cancer cases combined (14% versus 8% and 5% respectively).

Lung diseases include chronic obstructive pulmonary disease (COPD), asthma, lung cancer, cystic fibrosis, pulmonary fibrosis and sleep disorders.

Urgent Measures The Society welcomes accelerated implementation of the Sláintecare Strategy as set out in the Programme for Government but is calling for this to encompass a targeted response to the specific challenges of respiratory healthcare through a range of measures. These include: • Staffing: increased numbers of respiratory specialists to deliver timely care in the most appropriate setting at both community and hospital level, including respiratory doctors, nurses, physiotherapists and respiratory physiologists • Infrastructure: investment and adaptation of infrastructure with availability of isolation rooms, negative pressure rooms and adequate space and

streaming systems in hospitals to allow for physical distancing and management of high-risk patients • Technology: continued development and application of technology and innovation to provide virtual solutions for clinical management, monitoring and self-care of patients • Guidelines: urgent implementation of the most recent Irish Thoracic Society guidelines in all hospitals Potential Lung Health Crisis at Scale Not Yet Seen Dr Aidan O'Brien, President, Irish Thoracic Society, comments, “It is clear that we are storing up a backlog of undiagnosed and untreated respiratory disease at a magnitude that will have untold implications for the healthcare service and for our patients in the coming months and years unless urgent action is taken. The stark reality of delayed access to care for people with lung disease is deteriorating health, reduced quality of life and, sadly, in some cases, premature death.

“We commend the Herculean efforts of our colleagues throughout the healthcare system in retaining access to non-COVID-19 healthcare as much as possible while addressing the specific challenge of COVID-19 through separate access streams, virtual consultations and other innovative solutions.

“However, in order to prevent a future lung health crisis at a scale not yet seen in this country, we need to harness this capacity for transformation, innovation and investment to ensure that our patients can access timely multidisciplinary specialist care at community and hospital levels.

“Our patients have heeded Government advice by cocooning and self-managing their way through this emergency. They have played a crucial role in ensuring that our hospitals have not become overwhelmed. We now need to ensure that this sacrifice has not been at a longterm cost to their own health and that all patients receive equality of treatment and care into the future.”

umeclidinium/vilanterol

HAS POSITIVE HEAD-TO-HEAD DATA VS. ANOTHER ONCE-DAILY LAMA/LABA* 1 In symptomatic patients with moderate COPD *Anoro Ellipta compared to tiotropium/olodaterol showed statistical superiority on pre-specified secondary endpoint of trough FEV1 at 8 weeks in the Intent to Treat population. ITT population n=236 (180mL vs. 128mL in trough FEV1; Difference 52ml (p<0.001, 95% CI:28,77).

An 8-week, randomised, open-label, two-period crossover in symptomatic patients with moderate COPD (post bronchodilator FEV1 ≤70% and ≥ 50% of predicted value, mMRC≥2) and not receiving ICS at inclusion.1

The primary endpoint of non-inferiority on trough FEV1 at Week 8 in the PP population was met. Non-inferiority was met for the primary endpoint at Week 8 in the PP population (n=227) (175mL Anoro Ellipta and 122mL tiotropium/olodaterol, 95% CI: 26, 80; p<0.001)1

COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in 1 second; LABA, long-acting beta2-agonist; LAMA, long-acting muscarinic antagonist; mMRC, modified Medical Research Council scale; ITT, intent to treat; PP, per protocol.

Learn more by visiting: www.anoro.ie/headtohead Anoro Ellipta is contraindicated for patients who are hypersensitive to the active substances or to any of the excipients. Anoro Ellipta is not indicated for the treatment of acute episodes of bronchospasm.

Cardiovascular events, such as cardiac arrhythmias, may be seen after the administration of muscarinic receptor antagonists and sympathomimetic agents, including umeclidinium/vilanterol.

Therefore, Anoro Ellipta should be used with caution in patients with severe cardiovasular disease.

Due to antimuscarinic activity (i.e. LAMA class activity), umeclidinium/vilanterol should be used with caution in patients with urinary retention or with narrow-angle glaucoma.2

Anoro Ellipta 55/22mcg is indicated as a maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD)2

▼This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information.

Anoro®▼ Ellipta® (umeclidinium bromide/vilanterol [as trifenatate]) Prescribing information (Please consult the full Summary of Product Characteristics (SmPC) before prescribing) Anoro® Ellipta® 55/22mcg (umeclidinium bromide/ vilanterol [as trifenatate]) inhalation powder. Each single inhalation of umeclidinium bromide (UMEC) 62.5 micrograms (mcg) and vilanterol (VI) 25mcg provides a delivered dose of UMEC 55mcg and VI 22mcg.

Each delivered dose contains approx. 25 mg lactose.

Indications: COPD: Maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD. Dose and administration: Inhalation only.

COPD: One inhalation once daily at the same time of the day. Contraindications: Hypersensitivity to the active substances or to any of the excipients (lactose monohydrate and magnesium stearate). Precautions: Anoro Ellipta should not be used in patients with asthma.

Treatment with Anoro Ellipta should be discontinued in the event of paradoxical bronchospasm and alternative therapy initiated if necessary. Cardiovascular effects may be seen after the administration of muscarinic receptor antagonists and sympathomimetics therefore Anoro Ellipta should be used with caution in patients with severe cardiovascular disease. Anoro Ellipta should be used with caution in patients with urinary retention, narrow angle glaucoma, convulsive disorders, thyrotoxicosis, hypokalaemia, hyperglycaemia and severe hepatic impairment. No dose adjustment is required in

renal or mild to moderate hepatic impairment. Patients with rare hereditary problems of galactose intolerance, the Lapp total lactase deficiency or glucose-galactose malabsorption should not use Anoro Ellipta. Acute symptoms: Anoro Ellipta is not indicated for acute episodes of bronchospasm. Warn patients to seek medical advice if short-acting inhaled bronchodilator use increases, a re-evaluation of the patient and of the COPD treatment regimen should be undertaken. Interactions with other medicinal products: Interaction studies have only been performed in adults. Avoid β-blockers.

Caution is advised when co-administering with strong CYP3A4 inhibitors (e.g. ketoconazole, clarithromycin, itraconazole, ritonavir, telithromycin). Anoro Ellipta should not be used in conjunction with other longacting β2-adrenergic agonists or medicinal products containing long-acting muscarinic antagonists. Caution is advised with concomitant use with methylxanthine derivatives, steroids or non-potassium-sparing diuretics as it may potentiate possible hypokalaemic effect of β2-adrenergic agonists. Fertility, pregnancy, and breast-feeding: No available data. Balance risks against benefits. Side effects: Common: Urinary tract infection, sinusitis, nasopharyngitis, pharyngitis, upper respiratory tract infection, headache, cough, oropharyngeal pain,

References: 1. Feldman G.J et al. Adv Ther. 2017 Nov;34(11):2518-2533. 10.1007/s12325-017-0626-4.

2. Anoro Ellipta Summary of Product Characteristics. Available from: www.medicines.ie. Accessed: January 2020.

ANORO ELLIPTA was developed in collaboration with ©2020 GSK group of companies. All rights reserved.

constipation and dry mouth. Uncommon: Hypersenstivity reactions including rash, tremor, dysgeusia, dysphonia, atrial fibrillation, supraventricular tachycardia, rhythm idioventricular, tachycardia, supraventricular extrasystoles and palpitations. Rare: Anaphylaxis, angioedema, urticaria, vision blurred, glaucoma, intraocular pressure increased, paradoxical bronchospasm, urinary retention, dysuria and bladder outlet obstruction. Frequency not known: Dizziness. Marketing Authorisation (MA) Holder: GlaxoSmithKline (Ireland) Limited, 12 Riverwalk, Citywest Business Campus, Dublin 24, Ireland. MA Nr: 55/22mcg 1x30 doses [EU/1/14/898/002]. Legal category: POM B. Last date of revision: October 2019. Job Ref: PI-3826. Further information available on request from GlaxoSmithKline, 12 Riverwalk, Citywest Business Campus, Dublin 24, Tel: 01-4955000.

Adverse events should be reported to the Health Products Regulatory Authority (HPRA) using an Adverse Reaction Report Form obtained either from the HPRA or electronically via the website at www.hpra.ie.

Adverse reactions can also be reported to the HPRA by calling (01) 6764971. Adverse events should also be reported to GlaxoSmithKline on 1800 244 255.

Anoro and Ellipta are registered trademarks of the GlaxoSmithKline group of companies PM-IE-UCV-ADVT-200001 Date of Preparation: January 2020

20 News

ASCO 2020: New Drug Class in Multiple Myeloma Dr Paul Richardson, R.J. Corman Professor of Medicine Harvard Medical School and Dana-Farber Cancer Institute

A new type of myeloma treatment called CC-92480 (a CELMoD) showed benefit in a Phase I international clinical trial at the recent ASCO 2020 meeting.

This new class of drugs being developed in multiple myeloma called CELMoDs are functionally different from the immunomodulators like Revlimid and Pomalyst.

CELMoDs are larger molecules and work by quickly degrading a

specific set of proteins (called Ikaros and Aiolos). They are potent modulators of the cereblon E3 ligase complex.

They also stimulate the immune system and kill myeloma cells directly, even for myeloma that has become resistant to certain therapies. It is synergistic with other therapies and has "excellent tumor penetration" according to Paul Richardson, MD of the Dana Farber Cancer Institute. The other CELMoD currently in development is iberdomide.

Dr Paul Richardson, R.J. Corman Professor of Medicine Harvard Medical School and Dana-Farber Cancer Institute, shared more information about the study on a recent Myeloma Crowd Radio program, “It’s important to not think of them as sort of again a glorified IMiD. That would be a mistake. They are really in a different category in my opinion. I think this supports that. They have a much high degradation efficiency, the induction of apoptosis is much more powerful and they overcome lenalidomide and pomalidomide resistance nicely, pre-clinically, and 220 iberdomide has been the lead CELMoD presented on that last ASCO by Dr. Sagar Lonial.”

According to Dr. Richardson, the CC-92480 drug is more potent than iberdomide. In the study, 90% of patients were refractory (resistant) to lenalidomide and pomalidomide, all had received proteasome inhibitors and 70% were refractory

to monoclonal antibodies (like daratumumab or isatuximab).

The major side effects were neutropenia (low white blood cells) and thrombocytopenia (low platelet counts), but according to Dr. Richardson they were manageable.

Through the Phase I study, they found the Maximum Tolerated Dose was one milligram pill once a day, three weeks on, one week off, as the best schedule (after analyzing many schedules and reviewing the Ailos degradation and light chain measurements).

In those patients there was a 55% response rate (this is quite high for a single drug with patients who were this heavily pre-treated. Other recently approved drugs have been in the 30-35% range). According to Dr. Richardson: If you look at the 55% group, seven of the 11 patients in the cohort were classically pentarefractory. Of those seven patients who were penta-refractory, one had a complete response, one had a very good partial response, and two of the patients have partial responses, and one a minimal response, so you can see why we’re excited because that’s a very nice early signal.

Commitment to stop Asthma deaths SarahO'Connor, CEO Asthma Society of Ireland

The Asthma Society of Ireland has launched Stopping Asthma Deaths in Ireland, the organisation’s new 2020-2025 Strategic Plan, which commits to bringing an end to asthma deaths by 2030. 380,000 people currently have asthma in Ireland. At least one person with asthma dies every week in Ireland due to the disease, with an estimated 90 per cent of these deaths believed to be preventable.

Sarah O’Connor, CEO of the Asthma Society of Ireland, said, “The core focus of our work until 2030 will be eradicating asthma deaths. While we do know that the vast majority of asthma deaths are preventable in Ireland, there is not sufficient data to precisely identify what is causing them. This leaves healthcare planners uninformed and patients at unnecessarily high risk. It is critical that the Minister for Health commits to conducting a comprehensive investigation into asthma deaths and to publishing a plan to drastically reduce asthma deaths in Ireland.”

As the organisation embarks on its fifth decade, the Asthma Society’s new five-year strategic plan is

JUNE/JULY 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

intentionally ambitious. CEO Sarah O’Connor joined the organisation in February 2018 and has set about making the Asthma Society a force for change in the Irish healthcare landscape. It quickly became clear to Sarah that every action taken in the organisation was ultimately an integral step to, not just improving the lives of people with asthma, but saving their lives. The new strategic plan for the organisation brings together its health promotion, education, advocacy, awareness and fundraising functions to deliver the best services possible for asthma patients.

Sarah O’Connor continued, “We know that asthma can be mistakenly considered – including by some patients and medical professionals – a harmless condition experienced in early childhood. Although asthma can be easily managed for many people living with the disease, it can severely impede patients’

physical, mental and financial well-being and, without proper treatment, can and at times does prove fatal.

“Without access to specialist care, regular medical reviews and tailored self-management plans, improved prescription protocols and access to lifechanging medications, people with asthma will continue to die.

We in the Asthma Society will continue to deliver best-in-class services and supports and to advocate on behalf of patients to secure financial supports. We are also more focused than ever on ensuring asthma patients are receiving equal access to the highest standard of care and are therefore calling on the incoming government to commit to a national review of asthma deaths in its programme for government.”

Since the coronavirus outbreak, the Asthma Society considers its work to be more critical than ever.

Prescribing Information (Ireland) SPIRIVA® RESPIMAT® (tiotropium)

22 News

Ireland ‘first’ for medical research “The National Preclinical Imaging Centre’s high resolution imaging technologies will allow the research community in Ireland to respond to future international research challenges and will provide important support infrastructure for SFI Research Centres, Irish academic institutes and industry collaborators,” commented Director of NPIC, Professor Annette Byrne, Head of the RCSI Precision Cancer Medicine Group, Department of Physiology and Medical Physics and Centre for Systems Medicine at RCSI University of Medicine and Health Sciences.

“The Centre’s resources will allow us to work more collaboratively on research projects with clinicians and on training initiatives in radiology, which are critical elements of translating laboratory research finding to improvements in patient care in clinical settings,” Prof. Byrne added.

Professor Annette Byrne, Director of National Preclinical Imaging Centre, Head of the RCSI Precision Cancer Medicine Group, Department of Physiology and Medical Physics and Centre for Systems Medicine at RCSI University of Medicine and Health Sciences

A new National Preclinical Imaging Centre (NPIC), which will provide enhanced research data to inform new clinical trials that aim to improve patient outcomes, has been awarded funding of ¤3.4 million under the Science Foundation Ireland (SFI) Research Infrastructure Programme.

The Centre, which is the first of its kind in Ireland, is being established and co-funded

by RCSI University of Medicine and Health Sciences, University College Dublin (UCD), and CÚRAM, the SFI Research Centre for Medical Devices, based at National University of Ireland Galway (NUI Galway).

The Centre’s imaging infrastructure will support the development of new therapeutics and diagnostics in human disease areas including cancer, neurology, dementia, psychiatry, cardiology, medical devices, diabetes, tissue engineering, nanomedicine and inflammatory disease.

The Centre will provide a national pre-clinical imaging resource open to all academic, industry and not-for-profit researchers and will have locations in Dublin (RCSI, UCD) and Galway (NUI Galway). NPIC establishes a national pre-clinical magnetic resonance (MR) facility, a national high-field preclinical MR/ chemical imaging platform and incorporates a high-resolution micro-computed tomography (CT) and optical imaging laboratory.

“This infrastructural funding provided by SFI, which is complemented by financial support from each of our partner institutions, along with in-kind contributions from industry, will provide an unparalleled national resource for advancing in vivo imaging. Our research in the area of precision oncology will benefit considerably from being able to image non-invasively tumour growth and spread, leading to improved understanding of disease and associated therapeutic options,” said Professor William Gallagher, Associate Director of NPIC, Director, UCD Conway Institute and Deputy Director, Precision Oncology Ireland.

“I am delighted to see the establishment of NPIC, as it will provide a significant boost to our existing capabilities across academic, industry and clinical networks allowing us to further progress medical device research and its clinical application in each of our disease target areas,” commented Professor Abhay Pandit, Associate Director of NPIC and Scientific Director at CÚRAM, the SFI Research Centre for Medical Devices at NUI Galway.

“RCSI is very pleased to co-fund the establishment of this National Preclinical Imaging Centre. We look forward to working with our partners to maximise outputs from this facility for the betterment of human health.

I would like to thank SFI for their support and congratulate all involved with the proposal,” commented Professor Fergal O’Brien, Director of Research and Innovation at RCSI University of Medicine and Health Sciences.

The SFI Award is co-funded by all three Universities (RCSI, UCD and NUI Galway) and the application was supported by a diverse number of academic, not-for-profit and industry collaborators across the island of Ireland including Trinity College Dublin, University College Cork, Technical University Dublin, Cancer Trials Ireland, Queens University Belfast, Pfizer, Roche, M2i Ltd and Boston Scientific.

JUNE/JULY 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

Inhalation solution containing 2.5 microgram tiotropium (as bromide monohydrate) per puff. Indication: COPD: Tiotropium is indicated as a maintenance bronchodilator treatment to relieve symptoms of patients with chronic obstructive pulmonary disease (COPD). Asthma: Spiriva Respimat is indicated as add-on maintenance bronchodilator treatment in patients aged 6 years and older with severe asthma who experienced one or more severe asthma exacerbations in the preceding year. Dose and Administration: COPD Adults only age 18 years or over: 5 microgram tiotropium given as two puffs from the Respimat inhaler once daily, at the same time of the day.

Asthma Adults and patients 6 to 17 years of age: 5 microgram tiotropium given as two puffs from the Respimat inhaler once daily, at the same time of the day. In adult patients with severe asthma, tiotropium should be used in addition to inhaled corticosteroids (≥ 800 μg budesonide/day or equivalent) and at least one controller. In adolescents (12 - 17 years) with severe asthma, tiotropium should be used in addition to inhaled corticosteroids (> 800 - 1600 μg budesonide/day or equivalent) and one controller or in addition to inhaled corticosteroids (400 - 800 μg budesonide/day or equivalent) with two controllers. For children (6 - 11 years) with severe asthma, tiotropium should be used in addition to inhaled corticosteroids (> 400 μg budesonide/day or equivalent) and one controller or in addition to inhaled corticosteroids (200 - 400 μg budesonide/day or equivalent) with two controllers. Contraindications: Hypersensitivity to tiotropium bromide, atropine or its derivatives, e.g. ipratropium or oxitropium or to any of the excipients; benzalkonium chloride, disodium edetate, purified water, hydrochloric acid 3.6 % (for pH adjustment). Warnings and Precautions: Benzalkonium chloride may cause wheezing and breathing difficulties; patients with asthma are at an increased risk for these adverse events. Not for the initial treatment of acute episodes of bronchospasm or for the relief of acute symptoms. Spiriva Respimat should not be used as monotherapy for asthma. Asthma patients must be advised to continue taking antiinflammatory therapy, i.e. inhaled corticosteroids, unchanged after the introduction of Spiriva Respimat, even when their symptoms improve.

Immediate hypersensitivity reactions may occur after administration of tiotropium bromide inhalation solution. Caution in patients with narrowangle glaucoma, prostatic hyperplasia or bladder-neck obstruction. Inhaled medicines may cause inhalation-induced bronchospasm. Tiotropium should be used with caution in patients with recent myocardial infarction < 6 months; any unstable or life threatening cardiac arrhythmia or cardiac arrhythmia requiring intervention or a change in drug therapy in the past year; hospitalisation of heart failure (NYHA Class III or IV) within the past year.

These patients were excluded from the clinical trials and these conditions may be affected by the anticholinergic mechanism of action. In patients with moderate to severe renal impairment (creatinine clearance ≤ 50 ml/min) tiotropium bromide should be used only if the expected benefit outweighs the potential risk. Patients should be cautioned to avoid getting the spray into their eyes. They should be advised that this may result in precipitation or worsening of narrow-angle glaucoma, eye pain or discomfort, temporary blurring of vision, visual halos or coloured images in association with red eyes from conjunctival congestion and corneal oedema. Should any combination of these eye symptoms develop, patients should stop using tiotropium bromide and consult a specialist immediately. Tiotropium bromide should not be used more frequently than once a day. Interactions: Although no formal drug interaction studies have been performed, tiotropium bromide has been used concomitantly with other drugs commonly used in the treatment of COPD and asthma, including sympathomimetic bronchodilators, methylxanthines, oral and inhaled steroids, antihistamines, mucolytics, leukotriene modifiers, cromones, anti-IgE treatment without clinical evidence of drug interactions. Use of LABA or ICS was not found to alter the exposure to tiotropium. The co-administration of tiotropium bromide with other anticholinergic-containing drugs has not been studied and is therefore not recommended. Fertility, Pregnancy and Lactation: Very limited amount of data in pregnant women. Avoid the use of Spiriva Respimat during pregnancy.

It is unknown whether tiotropium bromide is excreted in human breast milk. Use of Spiriva Respimat during breast feeding is not recommended.

A decision on whether to continue/discontinue breast feeding or therapy with Spiriva Respimat should be made taking into account the benefit of breast feeding to the child and the benefit of Spiriva Respimat therapy to the woman. Clinical data on fertility are not available for tiotropium. Effects on ability to drive and use machines: No studies have been performed.

The occurrence of dizziness or blurred vision may influence the ability to drive and use machinery. Undesirable effects: COPD: Common (≥ 1/100 to < 1/10) Dry mouth. Uncommon (≥ 1/1,000 to < 1/100) Dizziness, headache, cough, pharyngitis, dysphonia, constipation, oropharyngeal candidiasis, rash, pruritus, urinary retention, dysuria. Rare (≥1/10,000 to <1/1,000): Insomnia, glaucoma, intraocular pressure increased, vision blurred, atrial fibrillation, palpitations, supraventricular tachycardia, tachycardia, epistaxis, bronchospasm, laryngitis, dysphagia, gastrooesophageal reflux disease, dental caries, gingivitis, glossitis, angioneurotic oedema, urticaria, skin infection/skin ulcer, dry skin, urinary tract infection. Not known (cannot be estimated from the available data): Dehydration, sinusitis, stomatitis, intestinal obstruction including ileus paralytic, nausea, hypersensitivity (including immediate reactions), anaphylactic reaction, joint swelling.

Asthma: Uncommon (≥ 1/1,000 to < 1/100) Dizziness, headache, insomnia, palpitations, cough, pharyngitis, dysphonia, bronchospasm, dry mouth, oropharyngeal candidiasis, rash. Rare (≥1/10,000 to <1/1,000): Epistaxis, constipation, gingivitis, stomatitis, pruritus, angioneurotic oedema, urticaria, hypersensitivity (including immediate reactions), urinary tract infection.

Not known (cannot be estimated from the available data): Dehydration, glaucoma, intraocular pressure increased, vision blurred, atrial fibrillation, supraventricular tachycardia, tachycardia, laryngitis, sinusitis, dysphagia, gastrooesophageal reflux disease, dental caries, glossitis, intestinal obstruction including ileus paralytic, nausea, skin infection/skin ulcer, dry skin, anaphylactic reaction, joint swelling, urinary retention, dysuria. Serious undesirable effects consistent with anticholinergic effects: glaucoma, constipation, intestinal obstruction including ileus paralytic and urinary retention. An increase in anticholinergic effects may occur with increasing age. Prescribers should consult the Summary of Product Characteristics for further information on undesirable effects. Pack sizes: Single pack: 1 Respimat re-usable inhaler and 1 cartridge providing 60 puffs (30 medicinal doses); Single refill pack: 1 cartridge providing 60 puffs (30 medicinal doses).

Legal category: POM. MA number: PA 775/2/2. Marketing Authorisation Holder: Boehringer Ingelheim International GmbH, D-55216 Ingelheim am Rhein, Germany. Prescribers should consult the Summary of Product Characteristics for full prescribing information. Additional information is available on request from Boehringer Ingelheim Ireland Ltd, The Crescent Building, Northwood, Santry, Dublin 9. Prepared in October 2019.

Adverse events should be reported to the Health Products Regulatory Authority at www.hpra.ie or by email to medsafety@hpra.ie.

Adverse events should also be reported to Boehringer Ingelheim Drug Safety on 01 291 3960 or by email to PV_local_uk_ireland@boehringer-ingelheim.com

Prescribing Information (Ireland) SPIOLTO® RESPIMAT® (tiotropium and olodaterol) Inhalation solution containing 2.5 microgram tiotropium (as bromide monohydrate) and 2.5 microgram olodaterol (as hydrochloride) per puff.

Action: Inhalation solution containing a long acting muscarinic receptor antagonist, tiotropium, and a long acting beta2-adrenergic agonist, olodaterol.

Indication: Maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD). Dose and Administration: Adults only aged 18 years or over: 5 microgram tiotropium and 5 microgram of olodaterol given as two puffs from the Respimat inhaler once daily, at the same time of the day. Contraindications: Hypersensitivity to tiotropium or olodaterol or any of the excipients; benzalkonium chloride, disodium edetate, purified water, 1M hydrochloric acid (for pH adjustment); atropine or its derivatives e.g. ipratropium or oxitropium. Warnings and Precautions: Not for use in asthma or for the treatment of acute episodes of bronchospasm, i.e. as rescue therapy. Inhaled medicines may cause inhalation-induced paradoxical bronchospasm. Caution in patients with narrow-angle glaucoma, prostatic hyperplasia or bladder-neck obstruction.

Patients should be cautioned to avoid getting the spray into their eyes.

They should be advised that this may result in precipitation or worsening of narrow-angle glaucoma, eye pain or discomfort, temporary blurring of vision, visual halos or coloured images in association with red eyes from conjunctival congestion and corneal oedema. Should any combination of these eye symptoms develop, patients should stop using Spiolto Respimat and consult a specialist immediately. In patients with moderate to severe renal impairment (creatinine clearance ≤ 50ml/min) use only if the expected benefit outweighs the potential risk. Caution in patients with a history of myocardial infarction during the previous year, unstable or life-threatening cardiac arrhythmia, hospitalised for heart failure during the previous year or with a diagnosis of paroxysmal tachycardia (> 100 beats per minute) as these patients were excluded from the clinical trials. In some patients, like other beta-adrenergic agonists, olodaterol may produce a clinically significant cardiovascular effect as measured by increases in pulse rate, blood pressure and/or symptoms.

Caution in patients with: cardiovascular disorders, especially ischaemic heart disease, severe cardiac decompensation, cardiac arrhythmias, hypertrophic obstructive cardiomyopathy, hypertension, and aneurysm; convulsive disorders or thyrotoxicosis; known or suspected prolongation of the QT interval (e.g. QT>0.44 s); patients unusually responsive to sympathomimetic amines; in some patients beta2-agonists may produce significant hypokalaemia; increases in plasma glucose after inhalation of high doses. Caution in planned operations with halogenated hydrocarbon anaesthetics due to increased susceptibility of adverse cardiac effects. Should not be used in conjunction with any other long-acting beta2-adrenergic agonists.

Immediate hypersensitivity reactions may occur after administration.

Should not be used more frequently than once daily. Benzalkonium chloride may cause wheezing and breathing difficulties; patients with asthma are at an increased risk for these adverse events. Interactions: Although no formal in vivo drug interaction studies have been performed, inhaled Spiolto Respimat has been used concomitantly with other COPD medicinal products, including short acting sympathomimetic bronchodilators and inhaled corticosteroids without clinical evidence of drug interactions. The co-administration of the component tiotropium with other anticholinergic containing drugs has not been studied and therefore is not recommended.

Concomitant administration of other adrenergic agents (alone or as part of combination therapy) may potentiate the undesirable effects of Spiolto Respimat. Concomitant treatment with xanthine derivatives, steroids, or non-potassium sparing diuretics may potentiate any hypokalaemic effect of adrenergic agonists. Beta-adrenergic blockers may weaken or antagonise the effect of olodaterol. Cardioselective beta-blockers could be considered, although they should be administered with caution. MAO inhibitors, tricyclic antidepressants or other drugs known to prolong the QTc interval may potentiate the action of Spiolto Respimat on the cardiovascular system.

Fertility, pregnancy and lactation: There is a very limited amount of data from the use of tiotropium in pregnant women. For olodaterol no clinical data on exposed pregnancies are available. As a precautionary measure, avoid the use of Spiolto Respimat during pregnancy. Like other beta2-adrenergic agonists, olodaterol may inhibit labour due to a relaxant effect on uterine smooth muscle. It is not known whether tiotropium and/or olodaterol pass into human breast milk. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with Spiolto Respimat should be made taking into account the benefit of breast-feeding to the child and the benefit of therapy for the woman. Clinical data on fertility are not available for tiotropium or olodaterol or the combination of both components. Effects on ability to drive and use machines: No studies have been performed. The occurrence of dizziness or blurred vision may influence the ability to drive and use machinery. Undesirable effects: Uncommon (≥ 1/1,000 to <1/100): Dizziness, headache, tachycardia, cough, dysphonia, dry mouth. Rare (≥ 1/10,000 to <1/1,000): Insomnia, vision blurred, atrial fibrillation, palpitations, supraventricular tachycardia, hypertension, laryngitis, pharyngitis, epistaxis, bronchospasm, constipation, oropharyngeal candidiasis, gingivitis, nausea, stomatitis, hypersensitivity, angioedema, urticaria, pruritus, rash, arthralgia, back pain, joint swelling, urinary retention, urinary tract infection, dysuria. Not known (cannot be estimated from the available data): Nasopharyngitis, dehydration, glaucoma, intraocular pressure increased, sinusitis, intestinal obstruction ileus paralytic, dysphagia, gastrooesophageal reflux disease, glossitis, dental caries, anaphylactic reaction, skin infection and skin ulcer, dry skin.

Serious undesirable effects consistent with anticholinergic effects: glaucoma, constipation, intestinal obstruction including ileus paralytic and urinary retention. An increase in anticholinergic effects may occur with increasing age. The occurrence of undesirable effects related to beta-adrenergic agonist class should be taken into consideration such as, arrhythmia, myocardial ischaemia, angina pectoris, hypotension, tremor, nervousness, muscle spasms, fatigue, malaise, hypokalaemia, hyperglycaemia and metabolic acidosis. Prescribers should consult the Summary of Product Characteristics for further information on side effects. Pack sizes: Single pack: 1 Respimat re-usable inhaler and 1 cartridge providing 60 puffs (30 medicinal doses); Single refill pack: 1 cartridge providing 60 puffs (30 medicinal doses) Legal category: POM. MA numbers: PA 775/9/1.

Marketing Authorisation Holder: Boehringer Ingelheim International GmbH, D-55216 Ingelheim am Rhein, Germany. Prescribers should consult the Summary of Product Characteristics for full prescribing information.

Additional information is available on request from Boehringer Ingelheim Ireland Ltd, The Crescent Building, Northwood, Santry, Dublin 9. Prepared in October 2019

Adverse events should be reported to the Health Products Regulatory Authority at www.hpra.ie or by email to medsafety@hpra.ie.

Adverse events should also be reported to Boehringer Ingelheim Drug Safety on 01 291 3960 or by email to PV_local_uk_ireland@boehringer-ingelheim.com

Help reduce your patient’s carbon footprint with SPIOLTO® Respimat® tiotropium & olodaterol

This unique soft-mist inhaler, designed for efficient lung delivery, is also:1–5  Propellant free  Reusable with up to 6 cartridges

1st month

2nd

3rd

4th

5th

6th

Throwing away the Respimat® inhaler every month is a thing of the past Remember to prescribe refill cartridges

tiotropium

tiotropium

tiotropium & olodaterol

tiotropium & olodaterol

Prescribing Information for SPIRIVA® Respimat® can be found on the adjacent page

References: 1. Hochrainer D et al. J Aerosol Med Pulm Drug Deliv 2005;18(3):273–82. 2. Dalby R et al. Int J Pharm 2004;283(1–2):1–9. 3. Pitcairn G et al. J Aerosol Med 2005;18(3):264–72. 4. Hansel M et al. Adv Ther 2019;36(9):2487–92. 5. SPIOLTO® Respimat® Summary of Product Characteristics.

Date of preparation: February 2020

PC-IE-100744

26 Blood clots

Blood clotting a significant cause of death Professor James O'Donnell, Director of the Irish Centre for Vascular Biology, RCSI and Consultant Haematologist in the National Coagulation Centre in St James's Hospital, Dublin

A study led by clinician scientists at RCSI University of Medicine and Health Sciences has found that Irish patients admitted to hospital with severe COVID-19 infection are experiencing abnormal blood clotting that contributes to death in some patients.

The study, carried out by the Irish Centre for Vascular Biology, RCSI and St James's Hospital, Dublin, is published in the British Journal of Haematology.

The authors found that abnormal blood clotting occurs in Irish patients with severe COVID-19 infection, causing micro-clots within the lungs. They also found that Irish patients with

higher levels of blood clotting activity had a significantly worse prognosis and were more likely to require ICU admission.

“Our novel findings demonstrate that COVID-19 is associated with a unique type of blood clotting disorder that is primarily focussed within the lungs and which undoubtedly contributes to the high levels of mortality being seen in patients with COVID-19,” said Professor James O’Donnell, Director of the Irish Centre for Vascular Biology, RCSI and Consultant Haematologist in the National Coagulation Centre in St James's Hospital, Dublin.

“In addition to pneumonia affecting the small air sacs

within the lungs, we are also finding hundreds of small blood clots throughout the lungs.

This scenario is not seen with other types of lung infection, and explains why blood oxygen levels fall dramatically in severe COVID-19 infection.

“Understanding how these microclots are being formed within the lung is critical so that we can develop more effective treatments for our patients, particularly those in high risk groups.

“Further studies will be required to investigate whether different blood thinning treatments may have a role in selected high risk patients in order to reduce the risk of clot formation,” Professor O’Donnell said.

Emerging evidence also shows that the abnormal blood-clotting problem in COVID-19 results in a significantly increased risk of heart attacks and strokes.

Professor O’Donnell led the cross disciplinary study, with joint first authors Dr Helen Fogarty and Dr Liam Townsend, along with Consultants from multiple specialities within St James’s Hospital and researchers at RCSI University of Medicine and Health Sciences and Trinity College Dublin.

Further research on these findings will continue under Irish COVID-19 Vasculopathy Study (iCVS) which has been jointly funded by the Health Research Board and Irish Research Council as part of the Irish government’s COVID-19 Rapid Response Research Funding.

Ranked number one globally for Good Health and Well-being in the Times Higher Education (THE) University Impact Rankings 2020, RCSI University of Medicine and Health Sciences is an international not-for-profit university, with its headquarters in Dublin.

RCSI is exclusively focused on education and research to drive improvements in human health worldwide. It is among the top 250 universities worldwide in the THE World University Rankings (2020) and its research is ranked first in Ireland for citations. RCSI has been awarded Athena Swan Bronze accreditation for positive gender practice in higher education.

LIFELONG LEARNING IN PHARMACY The Lifelong Learing in Pharmacy International Conference will be held in Dublin from Sunday 27th to Wednesday 30th June, 2021.

The event will be held with the Royal College of Surgeons in Ireland at their campus located on St. Stephen’s Green in the Dublin city centre.

The LLLP conferences bring together international and national colleagues to share their interest and research in the area of pharmacy education and professional development. The conference facilitates participant access to high quality educational programs, internationally significant research and development, and world-renowned leaders in the field. The abstract submissions and registrations for the 2020 conference are automatically carried over to the 2021 conference, and there is an exciting programme covering all aspects of lifelong learning in pharmacy.

The theme of LLLP2021 is “The Journey of Learning” and this will be explored during the conference using the following sub-themes: 

Planning the Route – the stages of our learning journey



Provisions & Companions – things that help us in our journey



Destinations – where are we going?

Due to the ongoing COVID-19 pandemic, the Monash University Pharmacy Education Symposium has also been rescheduled, and is now due to take place in July 2022, with the theme of “Better Together.”

Visit https://lllpharm2021.com/ for further information.

JUNE/JULY 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

Clexane Safety Syringe designed to protect against needle stick injuries

Needle completely covered by the protection shield immediately after the injection

Automatic release of the safety mechanism when the plunger is fully depressed

Prescribing Information: Clexane® (enoxaparin sodium) & Clexane® Forte Solution for Injection in pre-filled syringes Please refer to the Summary of Product Characteristics (SmPC) before prescribing. Presentations: Clexane® single dose pre-filled syringes containing either: 2,000 IU (20mg) enoxaparin sodium in 0.2ml, 4,000 IU (40mg) enoxaparin sodium in 0.4ml, 6,000 IU (60mg) enoxaparin sodium in 0.6ml, 8,000 IU (80mg) enoxaparin sodium in 0.8ml or 10,000 IU (100mg) enoxaparin sodium in 1ml. Clexane® Forte single dose pre-filled syringes containing either: 12,000 IU (120mg) enoxaparin sodium in 0.8ml or 15,000 IU (150mg) enoxaparin sodium in 1ml. Indications: In adults for: prophylaxis of venous thromboembolic disease in moderate and high risk surgical patients, in particular those undergoing orthopaedic or general surgery including cancer surgery; prophylaxis of venous thromboembolic disease in medical patients with an acute illness (such as acute heart failure, respiratory insufficiency, severe infections or rheumatic diseases) and reduced mobility at increased risk of venous thromboembolism (VTE); treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), excluding PE likely to require thrombolytic therapy or surgery; prevention of thrombus formation in extracorporeal circulation during haemodialysis; treatment of unstable angina and non ST-segment elevation myocardial infarction (NSTEMI), in combination with oral acetylsalicylic acid; treatment of acute ST-segment elevation myocardial infarction (STEMI) including patients to be managed medically or with subsequent percutaneous coronary intervention (PCI). Dosage & Administration: Each pre-filled syringe is for single use only. Prophylaxis of VTE in Surgical Patients: With moderate risk of thromboembolism, recommended dose of enoxaparin sodium is 2,000 IU (20mg) once daily by subcutaneous (SC) injection. Initiation 2hrs before surgery was proven effective and safe in moderate risk surgery.

Treatment should be maintained for at least 7-10 days whatever the recovery status (e.g. mobility) and should be continued until the patient no longer has significantly reduced mobility.

In patients at high risk of thromboembolism, the recommended dose of enoxaparin sodium is 4,000 IU (40mg) once daily by SC injection preferably started 12hrs before surgery. Need for earlier than 12hrs enoxaparin sodium preoperative prophylactic initiation (e.g. high-risk patient waiting for a deferred orthopaedic surgery), the last injection should be administered no later than 12hrs prior to surgery and resumed 12hrs after surgery. For patients undergoing major orthopaedic surgery an extended thromboprophylaxis up to 5 weeks is recommended. For patients with high risk of VTE undergoing abdominal or pelvic surgery for cancer, extended thromboprophylaxis up to 4 weeks is recommended. Prophylaxis of VTE in Medical Patients: Recommended dose of enoxaparin sodium is 4,000 IU (40mg) once daily by SC injection. Treatment with enoxaparin sodium is prescribed for at least 6-14 days. Benefit is not established for treatment longer than 14 days. Treatment of DVT/PE: 150 IU/kg (1.5mg/kg) administered SC once daily should be used in uncomplicated patients with low risk of VTE recurrence. 100 IU/kg (1mg/kg) twice daily should be used in all other patients such as those with obesity, symptomatic PE, cancer, recurrent VTE or proximal (vena iliaca) thrombosis. The regimen should be selected based on individual assessment including evaluation of the thromboembolic risk and risk of bleeding. Enoxaparin sodium treatment is prescribed for an average period of 10 days. Oral anticoagulant therapy should be initiated when appropriate.

Treatment of Acute Coronary Syndromes: For treatment of unstable angina and NSTEMI, the recommended dose of enoxaparin sodium is 100 IU/kg (1mg/kg) every 12hrs by SC injection administered in combination with antiplatelet therapy. Treatment should be for a minimum of 2 days and until clinical stabilization (usual duration 2 to 8 days). Acetylsalicylic acid recommended for all patients without contraindications at an initial oral loading dose of 150–300mg (in acetylsalicylic acid-naive patients) and a maintenance dose of 75–325mg/day long-term. For treatment of acute STEMI, recommended dose of enoxaparin sodium is a single intravenous (IV) bolus of 3,000 IU (30mg) plus a 100 IU/kg (1mg/kg) SC dose followed by 100 IU/kg (1mg/kg) administered SC every 12hrs (maximum 10,000 IU (100mg) for each of the first 2 SC doses).

Appropriate antiplatelet therapy such as oral acetylsalicylic acid (75mg to 325mg once daily) should be administered concomitantly unless contraindicated. Recommended duration of treatment is 8 days or until hospital discharge. When administered in conjunction with a thrombolytic (fibrin specific or non-fibrin specific), enoxaparin sodium should be given between 15 minutes before and 30 minutes after the start of fibrinolytic therapy. For patients managed with PCI, if the last dose of enoxaparin sodium SC was given less than 8hrs before balloon inflation, no additional dosing needed. If the last SC administration was given more than 8hrs before balloon inflation, an IV bolus of 30 IU/kg (0.3mg/kg) enoxaparin sodium should be

+ m 700

D E T A 1 TRE E ID W D L R WO

administered. During haemodialysis: 100 IU/kg (1mg/kg) enoxaparin sodium introduced into arterial line of the circuit at beginning of dialysis. This dose is usually sufficient for a 4-hour session. If fibrin rings are found, e.g. after a longer session, a further 50 to 100 IU/kg (0.5 to 1mg/kg) may be given. In patients with high risk of haemorrhage reduce the dose to 50 IU/kg (0.5mg/kg) (double vascular access) or 75 IU/kg (0.75mg/kg) (single vascular access). Special Populations: Elderly ≥75 years of age: For treatment of acute STEMI, an initial IV bolus must not be used. Initiate dosing with 75 IU/kg (0.75mg/kg) SC every 12hrs (maximum 7,500 IU (75mg) for each of the first 2 SC doses only, followed by 75 IU/kg (0.75mg/kg) SC dosing for the remaining doses). Paediatric: Safety and efficacy not established. Renal impairment: Dosage adjustment required for patients with severe renal impairment (creatinine clearance 15-30 mL/min). Not recommended for patients with end stage renal disease (creatinine clearance <15 mL/min. Hepatic Impairment: Limited data in this population therefore caution should be used. Contraindications: Hypersensitivity to enoxaparin sodium, heparin or its derivatives, including low molecular weight heparins (LMWH) or any of the excipients. Recent (<100 days) history of immune mediated heparin-induced thrombocytopenia (HIT) or in the presence of circulating antibodies. Active clinically significant bleeding and conditions with a high risk of haemorrhage, including recent haemorrhagic stroke, gastrointestinal ulcer, presence of malignant neoplasm at high risk of bleeding, recent brain, spinal or ophthalmic surgery, known/ suspected oesophageal varices, arteriovenous malformations, vascular aneurysms/ major intraspinal/ intracerebral vascular abnormalities. Spinal/ epidural/ loco-regional anaesthesia when enoxaparin sodium is used for treatment in the previous 24hrs. Warnings and Precautions: Do not use interchangeably (unit for unit) with other LMWHs. History of HIT (>100 days) without circulating antibodies: Use with extreme caution in these patients and only after careful benefit-risk assessment and non-heparin alternative treatments are considered. Monitoring of platelet counts: There is a risk of antibody-mediated HIT, which is higher in postoperative patients and mainly after cardiac surgery and in patients with cancer. It is recommended that the platelet counts be measured before the initiation of therapy with enoxaparin sodium and then regularly thereafter during the treatment; or if clinical symptoms suggestive of HIT are experienced. Patients must be aware of the symptoms and told to inform their primary care physician if experienced. If a confirmed significant decrease of the platelet count is observed (30-50% of the initial value), enoxaparin sodium treatment must be immediately discontinued, and the patient switched to another non-heparin anticoagulant alternative treatment. Haemorrhage: Use with caution in conditions with increased potential for bleeding (e.g. impaired haemostasis, history of peptic ulcer, recent ischemic stroke, severe arterial hypertension, recent diabetic retinopathy, neuro- or ophthalmologic surgery, concomitant use of medications affecting haemostasis). Laboratory tests: Increases in activated partial thromboplastin time (aPTT) and activated clotting time (ACT) may occur at higher doses but not linearly correlated with increasing enoxaparin sodium antithrombotic activity. Spinal/epidural anaesthesia or lumbar puncture: must not be performed within 24hrs of administration of therapeutic doses of enoxaparin sodium; placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of enoxaparin sodium is low. Skin necrosis and cutaneous vasculitis: have been reported with LMWHs and should lead to prompt treatment discontinuation. Percutaneous coronary revascularization procedures: To minimize the risk of bleeding following the vascular instrumentation during the treatment of unstable angina, NSTEMI and acute STEMI, adhere precisely to the intervals recommended between enoxaparin sodium injection doses. It is important to achieve haemostasis at the puncture site after PCI. In case a closure device is used, the sheath can be removed immediately.

If a manual compression method is used, sheath should be removed 6 hours after the last IV/SC enoxaparin sodium injection. If the treatment with enoxaparin sodium is to be continued, the next scheduled dose should be given no sooner than 6 to 8 hours after sheath removal. The site of the procedure should be observed for signs of bleeding or hematoma formation. Acute infective endocarditis: Use of heparin is usually not recommended in patients with this condition. Mechanical prosthetic heart valves: Enoxaparin sodium has not been adequately studied for thromboprophylaxis in patients (including in pregnancy) with mechanical prosthetic heart valves. Elderly patients (especially >80 years old): may be at increased risk of bleeding complications at therapeutic doses. Hepatic impairment: Enoxaparin sodium should be used with caution in these patients. In patients with liver cirrhosis dose adjustment based on monitoring of anti-Xa levels is unreliable and not recommended. Renal impairment: There is

an increased risk of bleeding for these patients therefore careful clinical monitoring is advised and biological monitoring by anti-Xa activity measurement might be considered. Enoxaparin sodium is not recommended for patients with end stage renal disease. In patients with severe renal impairment (creatinine clearance 15-30 mL/min) a dosage adjustment is recommended for therapeutic and prophylactic dosage ranges. Low body weight patients: are at increased risk of bleeding at prophylactic and treatment dose ranges. Obese patients: are at higher risk for thromboembolism however there is no consensus for dose adjustment; these patients should be observed carefully. Hyperkalaemia: Heparins can suppress adrenal secretion of aldosterone leading to hyperkalaemia, particularly in patients such as those with diabetes mellitus, chronic renal failure, pre-existing metabolic acidosis, taking medicinal products known to increase potassium; plasma potassium should be monitored regularly especially in patients at risk. Traceability: In order to improve the LMWH traceability, it is recommended that health care professionals record the trade name and batch number of the administered product in the patient file. Sodium: For patients receiving doses >210mg/day, this medicine contains >24mg sodium, equivalent to 1.2% of the recommended maximum daily intake of sodium for an adult.

Pregnancy and Lactation: Enoxaparin sodium should be used during pregnancy only if the physician has established a clear need. Pregnant women receiving enoxaparin sodium should be carefully monitored for evidence of bleeding or excessive anticoagulation and should be warned of the haemorrhagic risk. If an epidural anaesthesia is planned, it is recommended to withdraw treatment before. Enoxaparin sodium can be used during breastfeeding. Interactions: Not Recommended: Systemic salicylates, acetylsalicylic acid at anti-inflammatory doses, and NSAIDs including ketorolac. Other thrombolytics and anticoagulants. Caution: Platelet aggregation inhibitors including acetylsalicylic acid used at anti-aggregant dose (cardioprotection), clopidogrel, ticlopidine, and glycoprotein IIb/IIIa antagonists indicated in acute coronary syndrome due to the risk of bleeding, Dextran 40. Systemic glucocorticoids. Medicinal products increasing potassium levels. Adverse Reactions: Very Common: Hepatic enzyme increases (mainly transaminases >3 times the upper limit of normality). Common: Haemorrhage, haemorrhagic anaemia, thrombocytopenia, thrombocytosis, allergic reaction, headache, urticaria, pruritus, erythema, injection site haematoma / pain / other reaction (such as oedema, haemorrhage, hypersensitivity, inflammation, mass, pain, or reaction). Uncommon: Hepatocellular liver injury, bullous dermatitis, local irritation, skin necrosis at injection site. Rare: Eosinophilia, cases of immuno-allergic thrombocytopenia with thrombosis (in some cases thrombosis was complicated by organ infarction or limb ischaemia), anaphylactic/anaphylactoid reactions including shock, spinal/neuraxial haematoma resulting in varying degrees of neurologic injuries including long-term or permanent paralysis, cholestatic liver injury, alopecia, cutaneous vasculitis, skin necrosis, injection site nodules, osteoporosis following therapy >3 months, hyperkalaemia. Please refer to the SPCs for full details. Legal Category: POM. Marketing Authorisation (MA) Numbers: Clexane 2,000IU: PA540/97/4; Clexane 4,000IU: PA540/97/5; Clexane 6,000 IU: PA540/97/6; Clexane 8,000 IU: PA540/97/7; Clexane 10,000 IU: PA540/97/1; Clexane Forte 12,000 IU: PA540/97/8; Clexane Forte 15,000 IU: PA540/97/2.

MA Holder and further information is available on request from: Sanofi Ireland Ltd., 18 Riverwalk, Citywest Business Campus, Dublin 24 or contact IEmedinfo@sanofi.com Tel: 01 403 5600. Date of Preparation: May 2020.

Adverse events should be reported.

Reporting forms and information can be found at: www.hpra.ie; E-mail: medsafety@hpra.ie Adverse events can also be reported to Sanofi Ireland Ltd. Tel: 01 403 5600.

Alternatively, send via Email to IEPharmacovigilance@sanofi.com Reference: 1. Data on File – Clexane IMS Data.

MAT-IE-2000431.

SPC dates: June 2018 (10,000 IU (100mg)/1ml) and June 2018 (15,000 IU (150mg)/1ml).

Date of preparation: June 2020.

28 Education: HIV

Covid-19 and Impact on HIV Furthermore, controversies still exist regarding the role of some antiretrovirals in preventing or treating COVID-19. The first randomised clinical trial with ritonavir-boosted lopinavir showed no benefit over standard care in 199 adults admitted to hospital with severe COVID-19.

In another cohort, eight of 947 individuals taking nucleoside reverse transcriptase inhibitors (NRTIs) plus non-nucleoside reverse transfer inhibitors (NNRTIs) were co-infected with SARS-CoV-2, with a similar rate to the general population in Wuhan, indicating that an NRTI plus NNRTI did not prevent COVID-19.

In the ongoing pandemic of COVID-19, nearly 5 million people have been diagnosed with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and more than 320 000 people have died. SARS-CoV-2 infection causes lymphopenia and immune-mediated cytokine storm syndrome, resulting in pathological changes in lungs, heart, liver, and other organs.1 People living with HIV-1 infection often have suppressed immune function and it is unknown how this might affect patients with SARS-CoV-2 coinfection.

Recent data have shown at least 490 patients with HIV-1 co-infected with SARS-CoV-2, of whom 287 were admitted to hospital and 50 died.

However, epidemiology, clinical characteristics, and outcomes for patients with HIV–SARSCoV-2 co-infection are not well understood.

Studies of SARS-CoV in 20032 and Middle East respiratory syndrome-CoV in 2015,3 suggest that patients with HIV often have lower risks of infection and progress to severe disease, which might be because of suppression of coronavirus replication by antiretroviral therapy (ART), but longer duration of disease, which might be because of their status of immune suppression. People with HIV might be at an increased

risk of SARS-CoV-2 infection or severe COVID-19, especially those with comorbidity, lower CD4 count, or high HIV RNA load.4 By contrast, the immunosuppression and low CD4 count might protect HIV1-infected individuals from developing the cytokine storm observed in patients with COVID-19.5 In The Lancet HIV, Pilar Vizcarra and colleagues present the infection rate and clinical characteristics of COVID-19 among 2873 HIV-infected individuals in Madrid, in whom there were 35 confirmed (with SARS-CoV-2 RT-PCR testing) and 16 clinically diagnosed cases of COVID-19.

The authors compared the characteristics of patients with HIV with or without SARS-CoV-2 infection. Among people with HIV, body-mass index was higher in those with COVID-19 (median 25·5 kg/m2 [IQR 22·1–28·0]) than in those without (23·7 kg/ m2 [21·5–26·0]; p=0·021). Chronic comorbidities were also more common in those with COVID-19: 32 (63%) of 51 compared with 495 (38%; p=0·0006), including hypertension (p<0·0001) and diabetes (p=0·0011).

Of the 51 HIV-infected individuals with COVID-19, the median most recent CD4 count was 565 cells

JUNE/JULY 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

per μL (IQR 296–782). All of them had received ART, and plasma HIV-RNA was fully suppressed (<50 copies per mL) in 50 patients (98%). Notably, previous administration of ART, nadir CD4 count, CD4/CD8 ratio, or preexisting comorbidities were not significantly different in recovered versus still-admitted individuals.

The rate of PCR-confirmed SARS-CoV-2 infection was 1·2% (95% CI 0·8–1·7) in the cohort of HIV-1-infected individuals, which is higher than the rate of 0·92% (0·91–0·93) in the Madrid general population.

Furthermore, the rate of infection was similar or slightly higher than that in an HIV-1-infected cohort in Wuhan Vizcarra and colleagues did not identify an association of the comorbidities with disease severity or outcomes. Similarly, nadir and recent CD4 count or CD4/CD8 ratio were not associated with disease severity.

These results do not support the idea that there is a higher COVID-19 infection rate or more severe disease course in people living with HIV than in HIVnegative people. Indeed, in the study by Vizcarra and colleagues, two of six critically ill individuals died and four survived. It is difficult to conclude that people with HIV with low CD4 counts might have worse outcomes than those with higher CD4 counts as previously speculated because of the small sample size.

In Vizcarra and colleagues' cohort, there was no difference in previous use of antiretrovirals in individuals with and without COVID-19. Neither nadir CD4 count nor the use of specific antiretroviral drugs affected the SARS-CoV-2 infection rate.

Another study found no evidence that pre-exposure prophylaxis is effective against COVID-19.

All the patients with HIV in this study were already on ART and viral replication was well controlled. Therefore, the findings might not be similar in HIV-infected patients with high viral loads, low CD4 cell count, or those who have not had ART. The effect of HIV-1 coinfection on the clinical course of COVID-19 has yet to be fully understood. More large cohort studies on coinfection with HIV and SARS-CoV-2 are needed to help understand prophylaxis of opportunistic infection for patients with low CD4 counts (<200 per μL); drug-drug interaction in coinfected patients; differences in CD4 declines during COVID-19 infection between HIV-infected patients and those without HIV infection; and the effect of SARSCoV-2 infection on HIV reservoirs.

So far, there is no evidence to support that people living with HIV have a higher COVID-19 infection rate or different disease course than those without HIV-1 infection.

References on request

30 Education: HIV

Irish Aids Day "We can end new HIV transmissions.....

We must ensure barrier free access to PrEP.….We can get to Zero"

“The Government should invest in the expansion of HIV testing services if it is serious about reversing record high newly notified HIV cases.” These were the words of Mr Stephen O’Hare, Executive Director with HIV Ireland as he spoke recently to coincide with the organisation’s new media messaging campaign to mark Irish AIDS Day, 15 June 2020.

Launched online due to the continued restrictions on public gathering imposed during Phase 2 of the Roadmap on Reopening Society and Business, the campaign seeks to promote the reevaluation of the current approach to ending HIV transmission in the wake of record high rates of newly notified cases of HIV and the Government’s robust response to the COVID-19 pandemic.

“Now, more than ever…” boasts the campaign messaging, “We must end HIV and HIV-related stigma”, “We can end new HIV transmissions”, “We must ensure barrier free access to PrEP.”, “We can get to Zero”, the last a reference to zero new HIV transmissions by the target date 2030 set out in the Sustainable Development Goals, to which Ireland has committed.

“The scale of the response to COVID-19 is unlikely to be repeated, unless the virus returns in more virulent waves” continued Mr O’Hare. “The impact on existing service provision, on our economy and on our society has been stark. There are, however, key lessons to be learned from this experience, which should inform the Government’s approach to HIV prevention, not least the critical value of widespread testing to detect and prevent onward transmission of the virus.”

New (provisional) data from the Health Protection Surveillance Centre indicates that for the third year in a row, the number of newly notified HIV cases continues to climb (536 in 2019 – the highest on record) with a corresponding increase in the rate of diagnoses (11.3 per 100,000 of the population). Data published weekly by the HPSC suggests a similar upward trajectory in 2020 with notified cases appearing to exceed the figure for the same period last year.

“The true impact of the lockdown, social distancing and the closure of recreational venues on rates of HIV transmission is not likely be known for some time following the widespread recommencement of testing,” said Mr O’Hare.

Covid-19 Tracker App The Department of Health and the Health Service Executive have published several important documents as part of the ongoing commitment to openness and transparency in the development of the Covid Tracker App for Ireland.

The Data Protection Impact Assessment (DPIA), the source code, the Product Explainer for the Covid Tracker App, and a series of app design and development reports are available on the HSE website.

As the country reopens, contact tracing and the early identification of symptoms, will become increasingly important as more people are visiting family and friends, exercising, socialising, shopping, returning to work and using public transport.

The Covid Tracker App will allow each individual to play an important part in controlling COVID-19, helping everyone to stay safe and protect each other.

The app will record if a user is in close contact with another user by exchanging anonymous codes that are held on the users’ phones.

People who test positive for coronavirus will be able to choose if they want to anonymously alert other app users who they have been in close contact with. In this way the app will augment the existing testing and tracing operation and enable the notification of close contacts that are unknown to each other.

The app will also allow the user to anonymously record information about how they feel every day.

The symptom tracker has the

JUNE/JULY 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

potential to generate valuable national data relevant to COVID-19. The accurate reporting of the timing of the first onset of symptoms will improve the speed and the accuracy of the tracing process.

Chief Information Officer (CIO) of the HSE Fran Thompson said, “The design of Covid Tracker App has been informed by a robust development and testing programme. The app development process here in Ireland has been led by the HSE and the Department of Health, in collaboration with the Government Chief Information Officer and An Garda Síochána, together with technical partners from the Irish private sector (Expleo, Nearform, Information Security Assurance Services Ltd. (ISAS), and EdgeScan) and scientific

partners from Science Foundation Ireland. Results from our testing programme have shown that the app was able to accurately detect 72% of close contacts using the Google Apple API.” This work at a national level has been situated in an unprecedented global collaboration between governments, industry and the scientific community. CEO of the HSE, Mr Paul Reid said, “The app will be an important part of our testing and tracing measures going forward. The app will augment the existing contact tracing operations by quickly notifying users if they have been a close contact of a confirmed case, enabling users to record symptoms, and providing a trusted source of information about COVID-19.”

Education: HIV 31

Global HIV Prevention Study ViiV Healthcare, the global specialist HIV company majority owned by GSK, with Pfizer Inc. and Shionogi Limited as shareholders, have announced the interim analysis of the HIV Prevention Trials Network (HPTN) 083 study evaluating the safety and efficacy of investigational, long-acting, injectable cabotegravir for HIV prevention.

In the study cabotegravir was found to be 69% more effective (95% CI 41%-84%) in preventing HIV acquisition in men who have sex with men (MSM) and transgender women who have sex with men when compared to the current standard of care, daily oral emtricitabine/tenofovir disoproxil fumarate 200 mg and 300 mg (FTC/TDF) tablets.

The study achieved its primary objective of non-inferiority with the difference approaching superiority in favour of cabotegravir, pending final analysis.

The HPTN 083 study, with approximately 4,600 participants across more than 40 sites in North and South America, Asia, and Africa, is one of the first-ever clinical trials to directly compare two active prevention agents.

In a planned interim review, the independent Data and Safety Monitoring Board (DSMB) found the study data clearly indicated that long-acting injectable cabotegravir was highly effective at preventing HIV in the study population. Among the 50 people in the trial who acquired HIV, 12 were randomised to the longacting cabotegravir arm and 38 were randomised to the daily, oral FTC/TDF arm. This translated to an HIV incidence rate of 0.38% (95% confidence interval [CI] 0.20%0.66%) in the cabotegravir group and 1.21% (95% CI 0.86%-1.66%) in the FTC/TDF group. Adherence to oral FTC/TDF was high, based on a random subset sampling that detected tenofovir (> 0.31 ng/ml) in 87% of all samples tested. Despite this high level of adherence to oral therapy, long-acting cabotegravir was 69% (95% CI 41%-84%) more effective than FTC/TDF in preventing HIV acquisition in the study population.

Myron S. Cohen, M.D., CoPrincipal Investigator of the

Myron S. Cohen, M.D., Co-Principal Investigator of the HPTN and the Yeargan-Bate Distinguished Professor of Medicine, Microbiology and Immunology and Epidemiology at the University of North

HPTN and the Yeargan-Bate Distinguished Professor of Medicine, Microbiology and Immunology and Epidemiology at the University of North Carolina (UNC) at Chapel Hill, said, “Each year, an estimated 1.7 million people are newly diagnosed with HIV. To lower that number, we believe more prevention options are needed in addition to currently available oral tablets for daily use. If approved, a new injectable agent, such as longacting cabotegravir administered every two months, could play an important role in reducing HIV transmission and helping to end the HIV epidemic.”

Safety was similar in the two groups. Most participants in the cabotegravir group (80%) reported pain or tenderness at the injection site, compared to only 31% of those in the FTC/ TDF arm, who received placebo injections. Discontinuation due to injection site reactions or injection intolerance in the cabotegravir arm of the study was 2% and there were no discontinuations due to ISRs in the FTC/TDF arm.

Following review of these findings, the DSMB recommended the blinded, randomised portion of the study be stopped early and results released. Participants who were in the FTC/TDF arm will be offered CAB LA and participants in the CAB LA arm will continue to receive it. Participants who do

not want to receive CAB LA will be offered FTC/TDF until the end of the originally planned blinded component of the study. The DSMB decision was approved by the U.S. National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), the study sponsor.

The HPTN 083 study enrolled HIVnegative men who have sex with men and transgender women who have sex with men, participants considered at risk for HIV acquisition. Two-thirds of study participants were under 30 years of age, and 12% were transgender women. Half of the participants in the United States identified as black or African American.

“These study results demonstrate that long-acting injectable cabotegravir dosed every two months can successfully reduce HIV acquisition in at-risk MSM and transgender women,” said Kimberly Smith, M.D., Head of Research & Development at ViiV Healthcare. “We are thrilled with the results not only because of the high efficacy of cabotegravir but also because we have demonstrated high efficacy in a study that adequately represents some of the populations most disproportionately impacted by HIV -- black MSM in the US, young MSM globally and transgender women,” she said.

“We continue to be focused on the completion of the companion HPTN 084 study, which will give us important information about the effectiveness of cabotegravir in women. New options are needed for HIV prevention that offer an effective alternative to daily oral PrEP. If approved, this long-acting injectable has the potential to be a game-changer for HIV prevention by reducing the frequency of dosing from 365 days to six times per year.”

HTPN 083 was jointly funded by the U.S. NIAID, part of the NIH, and ViiV Healthcare, and was conducted by the HPTN. Study product was provided by ViiV Healthcare and Gilead Sciences.

The DSMB also reviewed data from HPTN 084, which began a year later than HPTN 083, and recommended that it continue as planned. To date, more than 3,000 sexually active women in seven African countries have enrolled in HPTN 084, which is co-funded by NIAID, ViiV Healthcare and the Bill & Melinda Gates Foundation.

Detailed results from HPTN 083 will be presented at an upcoming scientific meeting. ViiV Healthcare plans to use the data from HPTN 083 for future regulatory submissions. Cabotegravir has not yet been approved for the treatment or prevention of HIV as a single agent by regulatory authorities anywhere in the world.

HOSPITALPROFESSIONALNEWS.IE | HPN • JUNE/JULY 2020

32 News

Updates within the Irish Medication Safety Network Paul Tighe, immediate past Chair of the Irish Medication Safety Network, with Minister for Health Simon Harris at the IMSN annual conference, 2018

• Update of Sound Alike Look Alike Drugs guidance, including a SALAD bar – list of reported drug pairs with potential for confusion. See https://imsn.ie/ sound-alike-look-alike-drugssalads-briefing-document/ • Update of Safety Alert Risks with IV Paracetamol available at https://imsn.ie/the-safe-use-ofiv-paracetamol/

Below, Niamh O’Hanlon, Chair of the Irish Medication Safety Network (IMSN) and Pat O’Brien, Deputy Chair, give Hospital Professional News readers an update on recent issues.

The Irish Medication Safety Network (IMSN) is a voluntary, independent group of hospital pharmacy based specialists with an interest in medication safety.

Recent IMSN publications include: • Collaboration with the HSE on presentation of medicines during COVID-19. See https:// imsn.ie/covid-19-drug-check/

Our principal aim is to improve patient safety with regard to the use of medicines by promoting the exchange of information on medication safety and facilitating national and global initiatives to help minimize risks to patients.

Left to Right: Professor Catherine Nugent, Head of Pharmacy, Beacon Hospital, Dr. Eileen Relihan, Medication Safety Facilitator, St James’s Hospital, Professor Ciarán Meegan, former Chair of the IMSN, Head of Pharmacy, MMUH, then Minister for Health Leo Varadkar, Niamh O’Hanlon, current Chair of the IMSN, and Professor Brian Cleary, Head of Pharmacy, Rotunda Hospital at the IMSN conference, 2014

JUNE/JULY 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

• For those hospitals in the early stages of building a medication safety profile, the IMSN document Building a Medication Safety Programme in a hospital in Ireland: Fundamental steps may be useful. See link https://imsn.ie/ building-blocks-document/ Upcoming IMSN publications: Imminent publications include: • updates of IMSN Best Practice

Guidelines of the Safe Use in Irish Hospitals of o insulin o IV potassium • With the changes in legislation regarding electronic transfer of prescriptions (S.I. No. 98/2020 and S.I. No 99/2020), the IMSN has established a short life working group with a focus on enabling safe transmission of hospital prescriptions electronically, and will publish guidance shortly.

Sincere thanks: The IMSN would like to sincerely thank Paul Tighe, immediate past chair of the IMSN & Head of Pharmacy at SVUH, for his leadership and dedication to the Network over the last 5 years.

The IMSN would also like to take the opportunity to thank Prof.

Ciarán Meegan, founding Chair of the IMSN & Head of Pharmacy at MMUH, for his commitment to the Network since its inception in 2007, and wish him a long and happy retirement.

For further information on guidance provided by the IMSN, please see our website www.imsn.ie

CPD 66: STROKE

33

AUTHOR:

Continuing Professional Development

CPD

Dr John Charles Corrigan; Consultant Stroke Physician and Geriatrician, Cavan and Monaghan RCSI Hospital Group; Honorary Consultant Neurologist Mater Misericordiae Hospital, Dublin; Stroke Physician on out of hours rota with Mater Misericordiae Hospital, Dublin; Registered BASP

1. REFLECT - Before reading this module, consider the following: Will this clinical area be relevant to my practice?

3. PLAN - If I have identified a knowledge gap - will this article satisfy those needs - or will more reading be required?

2. IDENTIFY - If the answer is no, I may still be interested in the area but the article may not contribute towards my continuing professional development (CPD).

If the answer is yes, I should identify any knowledge gaps in the clinical area.

4. EVALUATE - Did this article meet my learning needs - and how has my practise changed as a result?

Have I identified further learning needs?

assessment. Follow the 4 previous steps, log and record your findings.

Published by HPN. Copies can be downloaded from www.irishpharmacytraining.ie

Stroke: a Bleeding Dilemma 5. WHAT NEXT - At this time you may like to record your learning for future use or

Disclaimer: All material published is copyright, no part of this can be used in any other publication without permission of the publishers and author.

Introduction:

Stroke: a Bleeding Dilemma

The treatment of acute ischaemic stroke (AIS) is well established since the introduction of the National Clinical Programme for Stroke (NCPS) in 2010. Moreover, in terms of acute AIS it is moving very much in the direction taken in cardiology with primary percutaneous coronary intervention (PCI) recognising that the definitive treatment of AIS is to remove the clot. However with regard to It is the consequences of getting of haemostasis and the clotting Introduction: 60 Second Summary acute assessment and treatment thethis focus is stillwrong on thrombolysis the need well organised decision and causing andcascade andfor the amechanisms The treatment of acute ischaemic a fatal brain haemorrhage which with which the circulatory system which facilitates decision making.

The following article containspathway stroke (AIS) is well established attracts a lot of attention to the

responds to injury. Of course, it is

It is well worth having knowledge

ischaemic stroke (IS), injected

some thoughts on difficult since the introduction of the acute and stroke.

There a fatal worth remembering that bleeding It is the consequences of getting this treatment decision ofwrong causing brain haemorrhage which clinical decisions that I National Clinical Programme is much to be gained and much results for iatrogenic reasons have encountered in the attracts a lot of attention to the treatment acute stroke. is much to or beinappropriate gained anduse much for Stroke (NCPS) in 2010. at stakeof and this can result There in like over of at therapeutic management of Moreover, incan terms of acute AIS hesitation andregarding delay regarding antithrombotic drugs. stake and this result in hesitation and delay decision making.

It is important to acute ischaemic stroke. It is decision making. It is important it is moving very much in the formation intended to be educational remember therefore that this treatment is moretherefore likely tothat be this beneficialThe than not. of a clot in the to remember direction taken in cardiology with body is a complex process that but not comprehensive. The treatment is more likely to be primary percutaneous coronary involves multiple substances important message I feel is In relation to both treatment and prevention are many drugs involved and it will help to have beneficial there than not. intervention (PCI) recognising that called clotting factors that to be aware of the evidence the definitive treatment of AIS how they knowledge of their indications, work and interact with each other and with other agents.

In relation to both treatment and work together in a coagulation as much as possible and use is to remove the clot. However prevention there are many drugs cascade.

Anticoagulent agents the clinical skills you have It is well worth having knowledge of haemostasis and the clotting cascade and the mechanisms with with regard to acute assessment involved and it will help to have exert effects at various sites in learned to help with difficult which the circulatory system responds to injury. Of course, it is worththis remembering that bleeding and treatment the focus is still knowledge of their indications, pathway (Figure 1). Tissue scenarios and remember that on thrombolysis andreasons the needlike for over for iatrogenic orthey inappropriate use of antithrombotic drugs. how work and interact with plasminogen activator (tPA), with care treatment is more results a well organised pathway which each other and with other agents. currently licenced to treat likely to do good than not. facilitates decision making.

Figure 1: Major classes of anticoagulants include warfarin, heparin, direct thrombin inhibitors, and factors Xa inhibitors. This figure illustrates the sites within the coagulation cascade at which these major classes of anticoagulant exert their effects.

Figure 1: Major classes of anticoagulants include warfarin, heparin, direct thrombin inhibitors, and factors Xa inhibitors. This figure illustrates the sites within the coagulation cascade at which these major classes of anticoagulant exert their effects.

HOSPITALPROFESSIONALNEWS.IE | HPN • JUNE/JULY 2020

The formation of a clot in the body is a complex process that involves multiple substances called

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CPD 66: STROKE

into artery or vein will bind to fibrin in the thrombus and initiates fibrinolysis therefore dissolving the clot and restoring blood flow.

Getting the timing right i.e. within the recommended time window of 4.5 hours means that this ‘clot busting’ drug will have the best chance of dissolving a clot before it becomes established and before significant damage is done to the brain and where benefits still outweigh the risk of bleeding.

Unfractionated heparin (UFH) is a naturally occurring glycosaminoglycan and low molecular weight heparin (LMWH) is UFH, which has undergone fractionation in order to make its pharmacodynamics more predictable. It acts ‘indirectly’ at various sites in the coagulation cascade preventing the formation of clots and extension of existing clots. Unlike tPA it does not break down clots that have already formed. It allows the body’s natural clot lysis mechanisms to work normally to break down clots that have formed. Its indications include prophylaxis and treatment of thromboembolis disease, for

example, deep venous thrombosis (DVT) and pulmonary embolus (PE). Warfarin is a vitamin K antagonist (VKA) which is a synthetic anticoagulant that acts by inhibiting vitamin K-dependent coagulation Factors II, VII, IX and X. Unlike heparin and warfarin which act at multiple sites of the clotting cascade, direct oral anticoagulant (DOAC) agents are anticoagulant drugs that have only one site of action. Dabigatran is a direct thrombin (IIa) inhibitor and apixaban, edoxaban and rivaroxaban are factor Xa inhibitors. In terms of reversal of effect in ICH idarucizumab is approved as reversal agent for dabigatran and andexanet alfa or 4-complex PCC (prothrombin complex concentrate) for reversal of rivaroxaban, edoxaban and apixaban (Cuker et al, 2019).

Remember that reversal agents are prothrombotic and carry a risk of life-threatening thrombosis and should only be used in someone who is at imminent risk of death from bleeding.

JUNE/JULY 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

Antiplatelet drugs decrease platelet aggregation and inhibit thrombus formation.

Aspirin inhibits the enzyme cyclooxygenase reducing the production of thromboxane A2, a stimulator of platelet aggregation.

Clopidogrel is a thienopyridine that inhibits adenosine diphosphate-dependent platelet aggregration. They are used in primary and secondary prevention of thrombotic cerebrovascular and cardiovascular disease.

Antiplatelet drugs can reversibly or irreversibly inhibit platelet aggregation, one of the initiating steps in clot formation, resulting in a decreased tendency of platelets to adhere to each other and adhere to damaged blood vessel endothelium.

Regarding COVID 19, there are some suggestions in early studies of increased incidence of stroke but these tend to occur in cases associated with co-morbidities like hypertension and diabetes, this clouds the issue and further work is needed to clarify this.

Acute Ischaemic Stroke: Stroke is common and rehabilitation of victims is a huge national drain on resources both financially but also in terms of health service resources and in terms of the physical and emotional well being of carers in the community. Over 80% of strokes are ischaemic, that is, due to a blocked blood vessel with the remaining to a burst blood vessel or haemorrhage (Adams et al, 1993). Of the ischaemic strokes only a small percentage (10 to 20%) are suitable for thrombolysis. Key to success in the treatment of AIS is a well organised pathway that includes rapid assessment and access to imaging that prevents delays and allows appropriate selection of patients for treatment. Remember that outside the time window of 4.5 hours the risk of bleeding due to tPA outweighs the benefits of treatment. It is expected that each case will present unique difficulties to be overcome before a decision can be safely made, for example, a history of previous

35

stroke including intracranial (ICH) will raise concern. Patients may present late or wake up with their symptoms or already be using anticoagulant medications.

However the only absolute contraindication to thrombolysis is intracranial bleeding on the CT brain. Often the right decision is not to thrombolyse, however there should be a good reason not to offer this life saving treatment. Serious complications of treatment including ICH and allergic reaction may occur following treatment and patients need monitored in a high dependency area or high dependency stroke unit (HASU) for 72 hours following treatment.

TIAs and small strokes: When does a stroke become a TIA or when is a stroke too small to treat with thrombolysis? An NIHSS < 3 implies a small stroke but when vital functions are like speech or limb weakness are an issue it might still be reasonable to treat with thrombolysis. A TIA is an impending stroke and an opportunity for prevention. The first few weeks after a TIA or a small stroke is the time of greatest risk of recurrence and so dual antiplatelets (DAPT) is becoming the typical of treatment. However, here the risk of IS must again be weighted with the risk of causing bleeding by doubling antiplatelet

cover and so DAPT is usually limited to about three months after a TIA or small ischaemic stroke. DAPT is not an option for large strokes due to the risk of causing bleeding into the infarct (Clairborne el al, NEJM, 2018; Wang et al, NEJM, 2013).

For long term stroke prevention a single antiplatlet agent is recommended. The use of proton pump inhibitors is not routine among stroke physicians in preventing upper gastrointestinal bleeding but some would suggest that in the long run this is a cost effective option (Kaiser et al, 2019). More aggressive early anticoagulation for minor

(NIHSS<3), non-cardioembolic stroke or TIA, beyond treatment with DAPT, has been reviewed (Seiffge et al, 2020) but larger trials are recommended.

Atrial Fibrillation: Atrial fibrillation (AF) is relatively common in hospital medicine, its incidence increasing with age. It is associated with an increased risk of cardioembolic stroke which can largely be counteracted by oral anticoagulation (OAC) medication but this carries the risk ICH (Luengo-Fernandez et al, 2012).

In general, OAC medication is tolerated well but following an ICH treatment it must be

HOSPITALPROFESSIONALNEWS.IE | HPN • JUNE/JULY 2020

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CPD 66: STROKE

stopped. Where the indication for OAC still remains the risks of recommencing treatment must be weighed against the continued risk of cardioembolic stroke due to AF. Guidelines (Hawkes et al, 2018) are not explicit here but recommencing OAC should be considered depending on the case circumstances, for example, a spontaneous ICH might have greater chance of recurrence than a traumatic haemorrhage that is due to a fall. It is important to highlight out that antiplatelet agents give no protection against the risk of IS due to AF. Occasionally IS will occur despite OAC therapy and the question is what to do next? It is important to consider compliance as the cause of treatment failure and this needs to be discussed with the patient.

In the case of patients on DOACs the short elimination half-lives mean that even short periods of non-compliance may rapidly result in sub-therapeutic levels.

Although compliance with DOAC treatment is better than with VKA, compliance can be as bad as 1 in 3 adhering <80% of the time and although it is convenient that DOACs do not require monitoring greater effort should be made to follow up to prevent poor compliance (Ozaki et al, 2020).

In patients with AF who have an IS, despite being on OAC they are at a higher risk for recurrent ischaemic strokes.

Simply changing the type of anticoagulation was not associated with a reduced risk (Seiffge et al, 2020). The risks and benefits of adding an antiplatelet might be discussed with patients but this treatment is outside current guidelines.

Interestingly, while guidelines recommend anticoagulation for all AF patients over 75 years, the evidence for a net clinical benefit (NCB) is sparse and one study found the NCB of treatment decreases with advancing age due to the competing risk of death from other causes e.g. cancer. In general though, elderly patients have a lot to gain from OAC treatment to prevent IS in AF.

discontinuation of treatment and to reduce the risk of excessive bleeding during the procedure.

Long acting VKAs need to be stopped several days before a procedure and will take several days to become therapeutic again afterwards. Some authors have found that periprocedural bridging therapy does not significantly reduce thromboembolic events compared with no bridging, however, it significantly raised the risk of both major bleeding and minor bleeding (Kulkarni et al, 2019; Douketas et al, 2015 ).

The American College of Cardiology (2017) produced a decision pathway for VKA in non-valvular AF using a patient’s estimated stroke and bleeding risk to determine whether bridging was indicated. For example, bridging was not recommended with a CHA2DS2-VASc of four or lower and no history of stroke, TIA or systemic embolism owing to their low day-to-day risk of thromboembolism without anticoagulants. Clinicians need to decide on individual cases; it may be that parentral bridging anticoagulation is not indicated in setting of a CHA2DS2-VASc <4 and no recent history of stroke and it may be reasonable to simply resume warfarin therapy without bridging.

DOACs have shorter halflives than warfarin and it is likely parentral bridging is less of an issue. Some feel that heparin bridging does not make pharmacological sense given the short, 8-14 hour DOAC elimination half-lives, its association with increased bleeding and its questionable efficacy. The PAUSE study (Douketis et al, 2019), for example, demonstrated that periprocedural discontinuation of DOACs without administering a bridging agent was associated with low thromboembolic and bleeding rates.

The risks and benefits of bridging with a shorter acting agent like heparin are unclear and a plan needs to take account for all factors in each case.

Bridging Therapy:

ICH in the elderly and restarting OAC treatment:

‘Bridging Therapy’ is used prior to a procedure or surgery, where short acting heparin replaces anticoagulation to reduce the risk of thromboembolism due to

ICH accounts for 10 - 15% of all strokes and is associated with a high mortality rate of approximately 50% and a high functional dependency

JUNE/JULY 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

(approximately 2/3) in survivors.

It is a recognised side effect of antithrombotic treatment that the incidence of ICH increases with age; probably the result of changes to blood vessels that are part of the aging process.

Spontaneous ICH in the elderly can occur on a background of cerebral amyloid angiopathy (CAA) which tends to be lobular and in the general population hypertensive ICH tends to be in the region of the basal ganglia, thalamus or pons. The prevalence of both AF and of ICH due to CAA increases with age, confounding the problem of managing one without causing the other (Shah et al, 2019) and given the demographics of our western population, this is an issue which is likely to increase.

As mentioned above, Maximailano et al (2018) found that most published data show a net benefit in terms of IS prevention and mortality when anticoagulation is restarted.

Sometimes an aneurysm is noticed on CT brain, which raises the risk of causing ICH by treating with OAC (or indeed tPA). Again the individual circumstances need to be recognised but in general bleeding is made worse but not caused by antithrombotic treatment and the presence of an incidental aneurysm should not preclude treatment which is indicated.

and High-Risk TIA. NEJM 2018: 379:215-225 6.

Wang Y, Wang Y, Zhao X, Liu L, Wang D, Wang C, Wang C, Li H, Meng X, Cui L, Jia J, Dong Q. Clopidogrel with Aspirin in Acute Minor Stroke or Transient Ischemic Attack. NEJM 2013: 369:11-19

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Seiffge D, De Marchis GM, Koga M, Paciaroni M, Wilson D, Cappellari M, Macha K, Tsivgoulis G, Ambler G, Arihiro S, Bonati LH, Bonetti B, Kallmunzer B, Muir K, Bovi P Gensicke H, Inoue M, Schwab S, Yaghi S, Brown M, Lyrer, Takagi M,Acciarrese M, Jager HR, Polymeris AA, Toyoda K, Venti M, Traenka C, Yamagami H, Alberti A, Yoshimura S, Caso V, Engelter ST, Werring D. Ischaemic Stroke Despite Oral Anticoagulant Therapy in Patients With Atrial Fibrillation. Ann Neurol 2020

8.

Hawkes MA, Rabinstein A. Anticoagulation for atrial fibrillation after intracranial hemorrhage. Neurol Clin Pract 2018;8(1): 48-57

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Kulkarni SA, Fang MC. Bridging Anticoagulation Therapy: A Teachable Moment. MAMA Internal Medicine 2019: November 25

10. Douketis JD, Spyropoulos AC, Kaatz S, Becker RC, Caprini JA, Dunn AS, Garcia DA, Jacobson A, Jaffer AK, Kong DF, Schulmon S, Turpie AGG. Perioperative Bridging Anticoagulation in Patients with Atrial Fibrillation.

NEJM 2015;373:823-823

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HSE National Clinical Programme for Stroke (2010)

2.

Figure 1: Google: ‘Anticoagulent wikipaedia’; ‘coagulation cascade and major classes of anticoagulant’

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Cuker A, Burnett A, Triller D, Crowther M, Ansell J, Van Cott EM, Wirth D, Kaatz S. Reversal of Direct Oral Anticoagulants: Guidance from the Anticoagulation Forum. Am J Hematol 2019; 94(6):697-709

11. Douketis JD, Spyropoulos AC, Duncan J, Carrier M, Le Gal G, Tafur AJ, Vanassche T, Verhamme P, Shivakumar S, Gross PL, Lee AYY, Yeo E, Solymoss S, Kassis J, Le Templier G, Kowalski S, Blostein M. Shah V MacKay E, Wu C, Clark NP, Bates SM, Spencer FA, Arnaoutoglou E, Coppens M, Arnold DM, Caprini JA, Li N, Moffat KA, Syed Sm Schulman S. Perioperative Management of Patients with Ptrial Fibrillation Reciving a Direct Oral Anticoagulant. JAMA Intern Med 2019;179(11):1469-1478

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Adams HP Jr, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, Marsh EE 3rd.

Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial.

TOAST. Stroke. 1993;24(1):35.

12. Shah SJ, Singer DE, Fang MC, Reynolds AS, Eckman MH. Net Clinical Benefit of Oral Anticogulation Among Older Adults with Atrial Fibrill ation.

Circulation: Cardiovascular Quality and Outcomes 2019;12

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Claiborne Johnston S, Easton D, Farrant M, Barsan W, Conwit RA, Elm JJ, Kim AS, Lindblad AS, Palesch YY. Clopidogrel and Aspirin in Acute Ischemic Stroke

References

News 37 New Molecule identified for Type 1 Diabetes Scientists from institutions across Europe have identified a new molecule that could be used as a biological ‘marker’ in the early diagnosis of type 1 diabetes and signify whether a treatment is working or not.

Currently, screening for and diagnosing type 1 diabetes is done by measuring blood glucose levels and detecting autoantibodies (proteins that allow the immune system to attack and destroy beta cells). However, these ‘markers’ are often only detected when a person has already lost most of their insulin-producing beta cells.

The research, published in the journal Diabetologia, shows that the molecule miR-409-3p was reduced both in mice with a type 1-like condition and in people recently diagnosed with type 1 compared to their unaffected counterparts. Found to be involved in regulation of the immune response, levels of the molecule rose when mice with a type 1-like condition were treated with an immunotherapy.

In this research project, part-

funded by JDRF, a team of scientists wanted to find a new marker for type 1 diabetes that was present in the very early stages of the condition.

This way, a person could be diagnosed and treated much sooner, reducing their risk of complications associated with high blood glucose. It could also help scientists in developing treatments that protect beta cells from the immune system’s attack, by allowing them to intervene sooner to save more beta cells and improve glucose management.

Additionally, a new marker could allow researchers to monitor how well future treatments such as immunotherapy are working in people with type 1 diabetes.

The team began by measuring the levels of certain molecules in the blood and pancreas of either healthy mice or those with a condition similar to type 1 diabetes. They also investigated the biological importance of the molecules by measuring the effects of a known immunotherapy on levels of the molecules.

Next, they recruited three groups of participants: people who had been very recently diagnosed with type 1, people who didn’t have the condition but had a relative with type 1 diabetes, and people who didn’t have the condition and didn’t have a relative with type 1 diabetes. They then took blood samples from all the participants and looked at levels of the same molecules they looked at in the mice.

areas surrounding the beta cells of mice with a type 1-like condition compared to mice without the condition. When looking at human blood samples they found that the same molecule was also lower in those with recently-diagnosed type 1 diabetes compared to those without type 1. The molecule, called miR-409-3p, was also found to be involved in regulating certain mechanisms of the immune system.

The scientists found that levels of a particular protein molecule were lower in both the blood and the areas surrounding the beta cells of mice with a type 1-like condition compared to mice without the condition. When looking at human blood samples they found that the same molecule was also lower in those with recently-diagnosed type 1 diabetes compared to those without type 1. The molecule, called miR-409-3p, was also found to be involved in regulating certain mechanisms of the immune system.

On further investigation, the team found that levels of miR-409-3p increased in the blood of mice with a type 1-like condition following treatment with an immunotherapy to slow development of type 1 diabetes.

The scientists found that levels of a particular protein molecule were lower in both the blood and the

Although in its early stages, this research suggests that miR-4093p could be a new marker of early type 1 diabetes development, enabling us to diagnose and treat the condition sooner. Combined with experimental therapies to stop the immune attack, early detection could make it possible to save more beta cells, making it easier for people with type 1 diabetes to manage their blood glucose.

Epilepsy Discovery could lead to new Therapies Researchers have identified a critical new step in how brain cells function in people with one of the most common forms of epilepsy.

This could lead to new treatment approaches for people with drugresistant epilepsy.

Dr Tobias Engel, FutureNeuro, RCSI

The study was led by researchers at FutureNeuro, the SFI Research Centre for Chronic and Rare Neurological Diseases, hosted by RCSI University of Medicine and Health Sciences with colleagues at Severo Ochoa-Centre for Molecular Biology (CBMSO) of Madrid and Institute for Research in Biomedicine (IRB) of Barcelona.

Changes in gene activity are known to be important in the development of epilepsy.

Normally, a molecule called messenger RNA is produced when a gene is active. This becomes the template for the production of the proteins that brain cells use to function. A critical step is the addition of a short sequence called a poly(A) tail. This has never been studied before in epilepsy.

“Our discovery adds another piece to the puzzle to help us understand why gene activity is different in someone with epilepsy,” said Dr Tobias Engel, FutureNeuro Investigator and Senior Lecturer in the School of Physiology and Medical Physics at RCSI. “It is remarkable that so many active genes in the brain show a change in this polyadenylation

process. We believe that this could ultimately lead us to new targeted treatments, allowing us to investigate if we could stop a person from developing epilepsy.”

Epilepsy is one of the most common chronic brain diseases,

affecting over 65 million people worldwide. While current drug treatments are usually effective in suppressing seizures, they do not work in one third of people with epilepsy and have no effect on the underlying causes of the disease.

HOSPITALPROFESSIONALNEWS.IE | HPN • JUNE/JULY 2020

38 News One third of unused medicines are dangerously discarded One third of unused medicines in Ireland are either ‘flushed’ or thrown in bins according to new research from the Irish Pharmacy Union (IPU). This potentially dangerous revelation has led the IPU to call for the introduction of a national medicines recycling programme, known as a DUMP (Dispose of Unused Medicines Properly) scheme across the country to encourage people to

dispose of their unused or out-ofdate medicines safely.

Commenting on the findings, community pharmacist and IPU Vice-President Eoghan Hanly said, “There are real and significant risks to health and the environment from improperly disposing of medicines. Whether this is in bins or by flushing down sinks or toilets you are risking contaminating

water systems and damaging biodiversity. Ultimately it risks impacting crops, animals and potentially increasing antibiotic resistance among humans. The more widespread the practice the bigger the potential risks.

“These findings are alarming and should be a significant concern to the authorities in this country.

To combat this very real threat we

are calling on the HSE to urgently implement a nationwide DUMP scheme through local pharmacies to promote safe and appropriate disposal of medicines and allow for easy recycling of inhalers and other medicine devices. Given the low levels of awareness of the environmental risks, a DUMP scheme should include public awareness campaigns to boost compliance.”

New Appointments Announced Mr Emmet Cullen has started practice at the Bon Secours Hospital Galway.

Mr Cullen graduated from UCD in 2002 and went on to complete his basic surgical training through the Royal College of Surgeons in Ireland. Since then, he has continued to be actively involved in evidenced based research, having completed several research projects, book chapters and presented at both National and International meetings.

Mr Emmet Cullen, Bon Secours Hospital Galway

In 2011, Mr Cullen entered the higher surgical training programme in trauma and orthopaedics.

He was awarded the FRCS in Trauma and Orthopaedic Surgery with RCSI in November 2016, completed his HST in T&O in 2017 and then an arthroplasty/ sarcoma fellowship with the NHS in St. Albans and the Royal National Orthopaedic Hospitals

in Stanmore. Emmet has been working as a Consultant Trauma and Orthopaedic Surgeon at Galway University and Merlin Park Hospitals since returning from fellowship in 2018. He is currently working as part of the orthopaedic surgical service here as contracted to by the HSE and will move into full time private practice thereafter.

In other news, Dr Tom Crotty, a Consultant Histopathologist at St Vincent’s University Hospital, has been elected by the Medical Council to the vacancy of VicePresident brought about by the resignation of out-going Vice President, Dr Anthony Breslin.

Dr Breslin, a Specialist in Public Health Medicine in the North Western Area of the HSE, has been heavily involved in dealing with the challenges the health service has faced due to COVID-19. Due to this, and the likely future demands

on his time, he has not been able to dedicate the time he wishes to his role as Vice President but will remain on as a member of the Council and as Chairperson of one of our Committees.

Speaking after the election the President of the Medical Council, Dr Rita Doyle, said, “I congratulate Dr Crotty on his election as Vice-President. Tom brings broad experience to the role and has been a valuable member of the Council since his appointment in 2018.”

Newly elected Vice President, Dr Tom Crotty, said, “As a country and as a health service we currently face many continuing challenges due to COVID-19. I am looking forward to utilising my experience in this role to fulfil the aims of the Council of protecting patients and supporting doctors.”

Clonmel Healthcare appointed distributor for Thermacare® We are pleased to inform you that Clonmel Healthcare has been appointed the distributor for the brand ThermaCare® by Angelini’s ThermaCare® partner in Ireland Carysfort Healthcare.

Clonmel Healthcare will be distributing ThermaCare® from 1st July 2020.

ThermaCare® is a medical device which delivers controlled therapeutic heat for 8 hours, right to the site of pain.

For further information, please contact Clonmel Healthcare on 01 6204000 2020/ADV/THE/040H. Date prepared: June 2020

JUNE/JULY 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

IPHA News 39

Turning the Tide The graph is heading in the right direction. The trend shows that cases of COVID-19 are declining.

We are getting the virus under control – at least for now. We cannot rule out future spikes and we may well have to learn to live with the disease. Meanwhile, biopharmaceutical innovators, working with academia, health services and public research institutes, are making a big difference in three key areas: science, supply and support.

If there is be a breakthrough on vaccines or treatments to prevent or cure the virus, it will come through science. Collaborative research is our best chance of stopping the disease. Meanwhile, manufacturing sites are operating at full tilt, with changes made to complex supply chains so that patients still get their medicines.

While all that is happening, the industry is donating funding, expertise, treatments and time to charities, hospitals, patient groups, voluntary organisations and the health authorities.

We have tried to tell some of that story through a new series of usergenerated videos and social media assets that capture the industry’s response to the pandemic. Our first thoughts, though, are with everyone affected by COVID-19 – the families and friends of those who have died, the people who have been sick, and the workers who have lost jobs and had their incomes cut. The social and economic toll of the disease will last a long time. But there is hope and there will be healing.

Around the world, there are hundreds of clinical trials under way for potential treatments and vaccines. Experts say there are 133 treatments in development for potential use in the fight against COVID-19. There are eight candidate vaccines in clinical trials and a further 82 in pre-clinical stages of development. In Europe, this progress is underpinned by the EU’s robust intellectual property framework – the scaffolding for medicines innovation. It has enabled bold investments in new medicines and many of them are now being tested for their possible use in COVID-19 cases.

It is hoped that all this collaborative research, involving industry, governments and research institutes, will yield a breakthrough soon. Already, some experts predict that it will take a year to 18 months to develop, test, approve and manufacture a vaccine. That would be a record.

Written by: Bernard Mallee, Director of Communications and Advocacy at the Irish Pharmaceutical Healthcare Association

Bernard Mallee, Director of Communications and Advocacy at the Irish Pharmaceutical Healthcare Association

"It is hoped that all this collaborative research, involving industry, governments and research institutes, will yield a breakthrough soon. Already, some experts predict that it will take a year to 18 months to develop, test, approve and manufacture a vaccine.

That would be a record"

Usually, vaccines take years, if not decades, to develop.

This time, though, there are some accelerants in the process. The complete genome sequence of COVID-19 was quickly identified and shared. As well as that headstart, scientists know more through decades of experience with similar viruses such as MERS, SARS, influenza, HIV and Hepatitis C. The industry has invested billions in technologies that have dramatically shortened the time it takes to decode viruses and develop potential vaccines.

Companies are now better able to manufacture vaccines and treatments at speed and scale.

When breakthroughs come that are safe and effective, they must be affordable for healthcare systems.

They will need to be distributed and administered globally too.

Every country will want a vaccine.

Billions of doses daily will be needed to vaccinate the world.

So while industry, governments and public institutions are partnering on research efforts now, they will need to collaborate even closer on the distribution and administration plan for vaccines and treatments. Now is the time to start those conversations.

The search for vaccines and cures dominates the

conversation around the global biopharmceutical industry.

Less profiled is the difference companies are making at community level where they are helping local hospitals, charities and voluntary organisations to respond to the pandemic. This is social purpose at a time when it is most needed.

Johnson & Johnson is working with the South/South-West Hospital Group on a return-tonormal-care plan that could help some 300,000 patients. Novartis, Eli Lilly and Roche are funding or supplying personal protection equipment to hospitals. Reckitt Benckiser has donated 40,000 anti-bacterial products to the HSE for distribution to hospitals and nursing homes. Bayer is donating energy supplements to frontline healthcare workers and partnering with the Irish Heart Foundation on a follow-up service for stroke patients. Boehringer Ingelheim is making immediate impact funding available to charity partners and giving employees 10 days paid leave for voluntary relief efforts.

Roche employees are volunteering as contact tracers, as well as supplying personal protection equipment to local hospitals.

Ipsen is providing resources to help cancer patients manage their own care at home. There are many other examples.

All of this is progress. But it must not detract from other strands of patient care. It is troubling that clinical trials – the engine room for new treatments – have been stalled by COVID-19. As well as that, there are signs that non-COVID-19 care has dropped dramatically. Some patients, many of them with cancer, heart disease or stroke conditions, are not going to hospital either because they are afraid or their procedures have been cancelled. It is vital that patients attend for appointments when they are available and that the health system has a plan for the surge in waiting lists in the coming months.

COVID-19 could be one of the turning points of the 21st century, even more influential than the 9/11 attacks in New York or the global financial crisis. The event itself is one thing; our response to it, together, is another. It casts the biopharmaceutical industry in a new light – the transformative potential of science, the essential nature of medicines manufacturing and supply, and the reach of small but important gestures of social support. This not over yet; it’s really only starting. But there has scarcely been a time for the biopharmaceutical industry to be more relevant and to have such a shaping influence on global events. It must use this time well.

HOSPITALPROFESSIONALNEWS.IE | HPN • JUNE/JULY 2020

40 Feature

Potential Impact of Cycle of Care on Diabetes Services in Secondary Care J Finnegan1, P McGing2, M Hatunic1 1 Endocrinology Department, Mater Misericordiae University Hospital, Dublin 2 Clinical Chemistry Department, Mater Misericordiae University Hospital, Dublin Diabetes Cycle of Care is an initiative introduced by the Health Service Executive (HSE). In this review we found that a quarter of patients attending a secondary care diabetes outpatient clinic in a large teaching hospital could potentially be managed in primary care upon implementation of Diabetes Cycle of Care.

T2DM on insulin was 64.3 mmol/ mol compared to 53.9 mmol/mol in their counterparts taking oral hyperglycaemic agents (OHA)/ diet control. Hba1c of ≤58 mmol/ mol was achieved by 51.6% of patients on insulin and 73.6% of patients taking OHA/diet alone.

In patients with T2DM the mean total cholesterol was 4.10 mmol/l and 72.4% of patients had LDL cholesterol of less than 2.6 mmol/l.

The majority of patients with T2DM are on a lipid lowering medication (71.4%). The prevalence of CKD was higher in patients with T2DM ; 30.2% have impaired renal function: 23.6% have stage III CKD (eGFR 30-59ml/min), 5.3% have stage IV CKD (eGFR 15-29ml/ min), and 1.3% have stage V CKD (eGFR <15ml/min). There were 65.1% patients with T2DM treated with an ACEi/ARB. Interestingly 122 patients (26.2%) attending clinics with T2DM on OHA/diet, with intact renal function (eGFR ≥60ml/min) had a Hba1c of ≤ 58 mmol/mol .

Discussion Introduction Prevalence of Type 2 diabetes (T2DM) is increasing internationally and nationally1,2. Diabetes and its associated complications account for a significant workload and financial burden to the health service3. Optimising glycaemic control and managing cardiovascular risk factors reduces the risk of developing complications associated with diabetes4. The endocrine service in the Mater Misericordiae University Hospital provides specialist care to over 8000 patients with diabetes.

As the prevalence of diabetes in Ireland is rising so is the demand for specialist care. The Diabetes Cycle of Care is a new initiative recently introduced by the HSE5.

It will provide bi-annual structured diabetes review, through primary care services, for patients with type 2 diabetes with stable glycaemic control6. Our objective was to assess the proportion of patients attending diabetes clinics that have T2DM and analyse how

many of them could potentially be suitable for the Cycle of Care.

Type 1 diabetes (T1DM) and twothirds T2DM (64.3%) (Table)

Methods

The average age of patients attending clinics with T1DM was 45.1 years. Mean HbA1c was 62.7(16.8SD) mmol/mol and 42.7% had an HbA1c of ≤58 mmol/mol.

Patients with T1DM had average total cholesterol of 4.44 mmol/l; 67.1% had LDL less than 2.6 mmol/l. There were 43.9% patients with T1DM on lipid lowering therapy. The majority of patients with T1DM had an eGFR >60ml/ min (80.5%), 7.3% had stage III CKD (eGFR 30-59ml/min) and 2.4% of patients had stage IV CKD (eGFR 15-29ml/min), just 32.3% were on an ACEi/ARB.

We retrospectively audited ten consecutive outpatient diabetes clinics. Patients’ medical data was obtained using the hospital’s Electronic Patient Record (Patient Centre). Results of the most recent bloods tests for HbA1c, Lipids, and eGFR was gathered from the Laboratory Information System (Telepath v1.9). Information on the patients’ age, type of diabetes, and treatment, was obtained from clinic letters on Patient Centre.

Data was analysed using Microsoft Excel to identify uncomplicated patients with T2DM, suitable for Cycle of Care, as per the ICGP guide including HbA1c <58 mmol/ mol and eGFR >60 ml/min6.

Results A total of 465 patients attended 10 diabetes clinics, approximately one-third (35.2%) of whom had

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Patients with T2DM had an average age of 62.9 years with mean HbA1c 56.1 (17.7SD) mmol/ mol. Just over a fifth (20.6%) of these patients were taking insulin, with 79.4% of patients using oral medication or diet to maintain glycaemic control. The average HbA1c in patients with

A high percentage (69.1%) of patients with T2DM achieved a target HbA1c of ≤ 58 mmol/mol and large numbers of patients were taking lipid lowering medication and ACEi/ARBs (65.1%). This review shows a significant number of patients with T2DM attending our specialist diabetes clinics are meeting their glycaemic targets. The majority of patients with T2DM are taking the appropriate medications to reduce cardiovascular risk.

Based on the data from this study 26.2% of patients currently attending the specialist diabetes outpatient clinics could be appropriately managed in primary care should the Cycle of Care be implemented. This positive development would allow specialist services to allocate more time and resources to managing patients with more complex disease.

References on request

Toujeo® is now available for your patients with diabetes mellitus from the age of 6 years*1 For the treatment of Type 1 and Type 2 diabetes mellitus from the age of 6 years1

Prescribing Information: Toujeo® (insulin glargine 300 units/ml) Please refer to Summary of Product Characteristics (SmPC) before prescribing.

Presentation: Toujeo SoloStar pre-filled pens each ml contains 300 units of insulin glargine. SoloStar pen contains 1.5ml (450 units) of solution for injection. DoubleStar pen contains 3ml (900 units) of solution for injection. Indication: Treatment of diabetes mellitus in adults, adolescents and children from the age of 6 years. Dosage and Administration: Toujeo is administered subcutaneously, by injection into the abdominal wall, the deltoid or the thigh, once daily, at any time of the day, preferably at the same time every day. The dose regimen (dose and timing) should be adjusted according to individual response. Do not administer intravenously. In type 1 diabetes mellitus, Toujeo must be combined with short-/ rapid-acting insulin to cover mealtime insulin requirements. In patients with type 2 diabetes mellitus, recommended daily starting dose is 0.2 units/kg followed by individual dose adjustments. Toujeo can also be given together with other antihyperglycaemic medicinal products. Switch between insulin glargine 100 units/ml and Toujeo: Insulin glargine 100 units/ ml and Toujeo are not bioequivalent and are not directly interchangeable. When switching from insulin glargine 100 units/ ml to Toujeo, this can be done on a unit to unit basis, but a higher Toujeo dose (approximately 10-18%) may be needed to achieve target ranges for plasma glucose levels. When switching from Toujeo to insulin glargine 100 units/ml, the dose should be reduced (approximately by 20%). Switching from other basal insulins to Toujeo: A change of dose and/ or timing of the basal insulin and concomitant anti hyperglycaemic treatment may be required. Dose adjustments may also be required if the patient’s weight or lifestyle changes, the timing of insulin dose is changed or other circumstances arise that increase susceptibility to hypo- or hyperglycaemia. Toujeo must not be mixed or diluted with any other insulin or other medicinal products. Close metabolic monitoring is recommended during a switch and in the initial weeks thereafter.

SoloStar 1-80 units per single injection in steps of 1 unit and DoubleStar 2-160 units in steps of 2 units. When changing from Toujeo SoloStar to Toujeo DoubleStar, if the patient’s previous dose was an odd number then the dose must be increased or decreased by 1 unit. Toujeo DoubleStar prefilled pen is recommended for patients requiring at least 20 units per day. Special Populations: Insulin requirements may be diminished in the elderly or patients with renal or hepatic impairment. Paediatric: When switching basal insulin to Toujeo, dose reduction of basal and bolus insulin needs to be considered on an individual basis, in order to minimise the risk of hypoglycaemia. The safety and efficacy of Toujeo in children and adolescents below 6 years of age have not been established. Contraindications: Hypersensitivity to insulin glargine or any excipients. Precautions and Warnings: Toujeo is not the insulin of choice for treatment of diabetic ketoacidosis. Hypoglycaemia: In case of insufficient glucose control or a tendency to hyper/hypoglycaemic episodes, the patient’s adherence to the prescribed treatment regimen, injection sites and proper injection technique

References: 1. Sanofi. Summary of Product Characteristics (Toujeo).

Date of preparation: February 2020 | SAIE.TJO.20.02.0063

and all other relevant factors must be reviewed before dose adjustment is considered. Particular caution should be exercised, and intensified blood glucose monitoring is advisable for patients in whom hypoglycaemic episodes might be of clinical relevance and in those where dose adjustments may be required. Warning signs of hypoglycaemia may be changed, less pronounced or absent in certain risk groups, potentially resulting in severe hypoglycaemia and loss of consciousness. Risk groups include patients in whom glycaemic control is markedly improved, hypoglycaemia develops gradually, an autonomic neuropathy is present, or who are elderly. The prolonged effect of subcutaneous insulin glargine may delay recovery from hypoglycaemia. Intercurrent illness: Requires intensified metabolic monitoring and often it is necessary to adjust the insulin dose. Insulin antibodies: administration may cause insulin antibodies to form. Use with pioglitazone: Cases of cardiac failure have been reported when pioglitazone was used in combination with insulin, especially in patients with risk factors for development of cardiac heart failure. If the combination is used, patients should be observed for signs and symptoms of heart failure, weight gain and oedema. Pioglitazone should be discontinued if any deterioration in cardiac symptoms occurs. Medication errors: Insulin labels must always be checked before each injection to avoid errors between Toujeo and other insulins. Patients must be instructed to never use a syringe to remove Toujeo from the SoloStar or DoubleStar pre-filled pen, A new sterile needle must be attached before each injection. Needles must not be re-used. Pregnancy and lactation: There is no data from exposed pregnancies in controlled clinical trials. However, there is a large amount of data on use of insulin glargine 100 units/ml in pregnant women indicating no specific adverse effects on pregnancy and no specific malformative nor feto/neonatal toxicity. The use of Toujeo may be considered during pregnancy, if clinically needed. Careful monitoring of glucose control is essential.

It is unknown if insulin glargine is excreted in breast milk. Interactions: Substances that affect glucose metabolism may require adjustment of insulin glargine. Adverse Reactions: Very common: Hypoglycaemia. Prolonged or severe hypoglycaemia may be life-threatening. Common: Lipohypertrophy, injection site reactions, including redness, pain, itching, hives, swelling, or inflammation. Legal Category: POM. Marketing Authorisation Number: SoloStar 3 Pen pack: EU/1/00/133/034, DoubleStar EU/1/00/133/038. Marketing Authorisation Holder: Sanofi Aventis Deutschland GmbH, D-65926 Frankfurt am Main, Germany. Further information is available from: Medical Information, Sanofi 18 Riverwalk, Citywest Business Campus, Dublin 24 or contact IEmedinfo@sanofi.com. Tel.: (01) 403 5600. Date of preparation: January 2020.

Adverse events should be reported. Reporting forms and information can be found at www.hpra.ie; email: medsafety@hpra.ie. Adverse events should also be reported to Sanofi Ireland Ltd. Tel: 01 403 5600.

Alternatively, send via email to IEPharmacovigilance@sanofi.com

42 Feature Identifying Crohn’s disease signal from variome analysis AUTHORS: Yanran Wang, Maximilian Miller, Yuri Astrakhan, Britt-Sabina Petersen, Stefan Schreiber, Andre Franke & Yana Bromberg - PART TWO: CONTINUED FROM MARCH Feature selected (FS) genes outperform Pascal genes in differentiating CDs from HCs We further evaluated the performance of the computationally extracted FS genes (DIS/DISO, KS5, TT5 and DKMcost sets; “Methods” section).

Trivially, the best performance (ROC/PR AUC = 1/1) was achieved by the DISO (Disease Overfitted) sets of more than 100 genes, defined as genes that were not affected in any of the CD-train HCs (“Methods” section).

Both the KS5max (all genes in KS5 set, ROC/PR AUC = 0.71/0.77, permutation pval = 0.033/0.022) and the DKMcost125 (top-ranked 125 genes from DKMcost set, ROC/PR AUC = 0.75/0.80, permutation pval = 0.014/0.010) models outperformed PascalGWAS175 (Fig. 2b, c). For the KS5 set, including more genes slightly improved performance (Fig. 2b). This was not the case for DKMcost, whose performance had reached a peak at 125 genes before dropping off. Note, however, that the maximum number of KS genes was 127, suggesting that models may simply not benefit from additional genes. TT5max and DISmax genes also had outperformed baseline, but were not as good as KS5max or DKMcost125 genes (Additional file 2: Figure S3). Also note that the FS sets were never overfitted to the data, as FS was performed in a leave-one-out fashion, i.e., excluding the testing individual.

Thus, our results suggest that FS selected genes can differentiate CDs from HCs in our data, particularly using rare variant

signal that is not available to the common variant-based methods.

Feature selection identifies known and previously unreported CD genes As described above, both PascalGWAS175 and FS sets (DKMcost125 and KS5max) performed well in differentiating CDs from HCs in the CD-train panel (Fig. 2).

However, the FS sets overlapped with PascalGWAS175 by no more than five genes (average pval > 0.25, hypergeometric test, in the background of ALL genes, Table 1). On the other hand, the KS5max set significantly overlapped with the DKMcost125 genes (over 57 genes; average pval = 6.64e−93). We also found that while the FS sets did not significantly overlap with most of the external sets (GWAS, MeSH, and PascalGWAS175), the external sets overlapped with each other (all with pval < 0.05, Table 1).

Note as an exception that while Swiss-Prot had no overlap with KS5max, the overlap of the former with DKMcost125 was significant (NOD243, MDR144, and DMBT145, three genes of only 18 in SwissProt), highlighting well-known CD genes extracted computationally without prior knowledge.

Our FS techniques identified some known (GWAS and MeSH) genes. For example, both FS sets contained the CD-associated LRRK246 and the uncharacterized KIAA110947 genes, which also appeared in GWAS and MeSH sets. Additionally, DKMcost125 genes NOD243, LSP148, 49, and CCR650 and KS5max genes IL198 and ATF451 also appeared in GWAS and MeSH. Overall,

however, few genes appeared both in the FS sets and in the experimentally derived external sets. The performance of the KS5max and DKMcost125 models thus suggests that computational FS methods are able to identify previously unsuspected CD genes.

CD-relevant genes interact We used gene set overrepresentation analysis to check if DKMcost125, KS5max, or PascalGWAS175 genes are enriched in known molecular pathways. FS found several significantly enriched, likely CDrelated, pathways that were not identified by PascalGWAS175, e.g., antimicrobial peptides, apoptosisrelated pathways, cGMP effects, neutrophil degranulation, and innate immune system (Additional file 4). The protein-protein interaction network of DKMcost125 genes (Fig. 3) suggested additional genes/proteins, which were not directly found by FS but may be relevant to CD, e.g., the TAF1 and the HNF4A transcription factors regulate many DKMcost125 genes, including the infamous NOD2.

HNF4A was annotated as CDassociated in previous studies52.

TAF1, on the other hand, needs further evaluation, but preliminary analysis shows that it contains a bromodomain, which may be critical in inflammation in general and bowel inflammation53,54,55.

Induced network of CD-train DKMcost125 genes. Interconnection of DKMcost125 genes through protein interaction and gene regulatory interaction. Magenta nodes were genes/proteins that were not selected by FS but interact with the FS genes

(black nodes) through protein or gene regulatory interactions.

Transcription factors TAF1 and HNF4A regulate many DKMcost125 genes, indicating their potential role in CD pathogenesis At high scoring thresholds, AVA,Dx precisely identifies people affected by Crohn’s disease Cutoff selection To select the cutoff in AVA,Dx score for calling an individual healthy or CD-affected, we plotted the prediction scores for each individual from CD-train in crossvalidation and selected a cutoff that best differentiated CDs from HCs (Fig. 4, Additional file 2). We chose three cutoffs as follows: (1) The default cutoff was set at 14.3 (“Methods” section), where we had balanced precision and recall for both CDs and HCs in our set (47 of 64 CD patients were correctly identified, as were 28 of 47 healthy controls; 71% precision, 73% recall, Matthews correlation coefficient (MCC) = 0.33). (2) To precisely identify CD, we set a stricter cutoff at 45, where 94% of the individuals above the cutoff were sick (27% recall). (3) On the other hand, to identify as many CD patients as possible, we set a cutoff at 0 where 89% of the CD patients were identified (70% precision). This tradeoff between precision and recall of predictions across thresholds suggest using the individual AVA,Dx scores to estimate the reliability of each prediction, i.e., it is more likely that the higher scoring individuals have CD than lower scoring ones. Note, however, that the score was not evaluated and should not be used as an indicator of disease severity.

Prediction of CD-train individuals using the DKMcost125 model in leave-one-out cross-validation.

Table 1 *Significant overlap between gene sets. The number of genes above the diagonal is the overlap between two sets. The corresponding overlap significance is below the diagonal (hypergeometric test in the background of ALL genes from the CD-train panel) **There were 109 cross-validation/ FS folds for each FS method (DKMcost125 and KS5max), i.e., 109 different gene sets. Here, the average fold size and range (in parenthesis) are displayed

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43 AUC = 0.69/0.92 (Fig. 5 and Table 2, permutation pval = 0.041/0.035, baseline PR AUC = 0.79). That is, at default cutoff, using this model, we were able to correctly identify 36 of 49 CD patients and 5 of 13 healthy controls (Table 2). Moreover, in predicting all WTCCC (CD) and GTEx (HC) individuals, the DKMcost125 model reached a ROC/PR AUC = 0.76/0.94 (Fig. 5 and Table 2, permutation pval < 0.001/0.001, baseline PR AUC = 0.82), while the PascalGWAS175 model failed to differentiate CD and HC (ROC/ PR AUC = 0.30/0.76). Our model identified HC individuals less accurately than CD patients, but better than the baseline (DKMcost125 model vs. baseline PR AUCs for HC were 0.35 vs.

0.21 and 0.31 vs. 0.18 for CD-test and WTCCC-GTEx panels, respectively).

Figure 3

Each dot represents one person in the panel, colored according to health status (red = CD, blue = HC).

Dots are jittered along the x-axis for better visualization. Dashed lines are the three cutoffs used for different levels of prediction stringency in calling an individual a CD patient. The predicted scores of CD and HC individuals were significantly different (KolmogorovSmirnov test p value = 0.0002226) For all further analyses, we built/used PascalGWAS175 and DKMcost125 prediction models using the entire CD-train panel, as opposed to leaving one sample out for cross-validation.

Batch effect across panels For AVA,Dx to be useful in diagnosis of new patients, the method has to be directly applicable to samples from different sequencing batches handled by different labs.

Regardless of health status, the sequencing procedures may cover different regions on the genome/ exome and potentially result in different numbers of variants even for the covered regions (Additional file 2: Section 7). This “batch effect” is a likely result of the use of diverse sequencing platforms and variant calling settings (Additional file 2: Tables S2 and S3). To evaluate the severity of the batch effect, we combined the ALL gene_score profiles of our CD-train panel with those of all other panels at our disposal (CD-test, WTCCC, and GTEx panels). We further performed principal component analysis on

the combined set. Individuals clustered precisely according to batch (Additional file 2: Figure S4), suggesting that our models could not be used for prediction of individual CD status in different batches. To test new individuals, batch effects had to be removed.

Moreover, to apply our method in a real-life situation, where only one individual is to be evaluated for CD at a time, the “batch” was designated as containing only one person. Thus, for each individual from the CD-test, WTCCC, and GTEx panels, we first extracted the loci covered by CD-train and then applied ComBat to adjust gene_ scores of the entire CD-train panel and the one testing individual.

We then built a new model using the adjusted CD-train panel for every testing individual—3379 models in total for the evaluation of all panels. Note that the AVA,Dx pipeline thus retrains the model to precisely fit the genomic data of every new test individual (an estimated 10 s per individual, on a 64-bit Mac iOS, with 2.9-GHz Intel Core i5 CPU and 16-GB DDR3 memory).

DKMcost125 model prediction of test set individuals. The predicted scores of all individuals from sets a CD-test panel and b WTCCC (all CD) and GTEx (all HC) panels combined. Dots are jittered along the x-axis for better visualization.

Dashed lines are cutoffs for calling an individual a CD patient (as in Fig. 4): loose (at 0), default (at 14.3), and strict (at 45). The predicted scores of CD and HC individuals were significantly different (Kolmogorov-Smirnov test p values a = 0.007413 and b < 2.2e−16, respectively) Discussion After years of study on the subject and numerous promising findings, CD risk prediction on the basis of genetic information still remains a problem. We developed AVA,Dx, a machine learning method that uses individual exome data of a panel of CD patients and healthy individuals to select CD-relevant genes and, potentially, predict the health status of previously unseen individuals. We first identified the functional effects of exome SNVs and combined them to create gene scores, indicative of gene functional deficiencies. This approach efficiently decreases the dimensionality of data from considering all exome variants (173,013 variants) to focusing only on affected genes (13,957 genes).

Figure 4

Evaluation of predictions For all evaluations, as for the training set, we retained only the EUR individuals from all test sets (see performance on non-EUR individuals in Additional file 2: Section 8). The PascalGWAS175 model was nearly random in predicting the status of all CDtest individuals (ROC/PR AUC of 0.57/0.82, Additional file 2: Figure S5). Our DKMcost125 model, however, reached ROC/PR

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44 Feature Additionally, FS techniques reveal new disease-related genes thus further reducing the dimensionality of data. While our method currently only considers coding variants, the path to integrating other CDrelevant types of variants, e.g., splice site and regulatory, into gene scoring is also clear.

The main idea behind AVA,Dx is that disease-causing variation is likely to be functionally detrimental to affected genes/pathway components. To evaluate whether molecular function disruption is an important indicator of gene involvement in disease, we tested a number of variant effect scoring schemes. Confirming our suspicion, we found that functional scoring was more informative than simple counting of relevant variants. Furthermore, as expected, models built using GWAS (with Pascal filtering) genes performed significantly better than random, indicating that GWAS indeed captures CD association successfully. On the other hand, our FS genes outperformed the GWAS genes, suggesting that variant functional effects are more likely to highlight causative, rather than association signals. Note, however, that AVA,Dx is not limited conceptually to the gene scoring described in this study; that is, other scores describing gene functional deficiency and including other variant types (e.g., regulatory or synonymous) and/or different genotype weighing and variant effect summation schemes can potentially be used.

Even as GWAS predictive accuracy improves, these studies are limited by large sample size requirements and use of only common SNPs. Thus, GWAS associations are often markers of disease, not causes, e.g., some disease-related genes may not be found simply because their variants are not common enough or are not covered by the SNP array. Our FS genes, on the other hand, are more informative of pathogenicity pathways, as they are selected on the basis of variation-driven gene functional changes that separate CD-affected individuals from healthy controls.

Interestingly, while both FS and GWAS gene-based models both perform well, the gene sets do not have much overlap, suggesting that FS identifies previously unknown CD-related genes. We also note that for other complex or rare diseases, where GWAS data is not available or informative, AVA,Dx may work uniquely to predict health status and identify pathogenicity pathways based on even a small number of whole exome sequences.

AVA,Dx required only 111 people to build a functional model (ROC AUC = 0.75). This was less than a tenth of the ~ 13,000 individuals that were needed in an earlier study to build a GWAS logistic regression model (reported ROC AUC = 0.86). Note that using only ~ 1300 people, significantly reduced the performance of this model (reported ROC AUC = 0.60)17. Thus, the number of individuals in this latter type of study clearly contributed heavily to its resolution of CD risk. Interestingly, when used with our CD-train panel, the logistic regression Wei et al. model (limited to exonic variants only) was able to correctly identify nearly three quarters (46 of 64 correct) of the patients but also misidentified more than half (21 of 47 correct) of the healthy individuals. On the other hand, AVA,Dx (at the default cutoff) identified just one less CD patient correctly (45 of 64 correct), but it did so at significantly higher accuracy—mislabeling only a third of the healthy individuals (28 of 47 correct).

For the larger WTCCC and GTEx panels, where > 80% of the 573 necessary GWAS loci were covered, the logistic regression model only reached 0.59 ROC AUC (a false positive rate of 86% at default cutoff; Additional file 2: Table S4). Similarly, polygenic risk scoring38 (PRS; all 230 CD loci, as described in the “Methods” section, were present in the WTCCC-GTEx panel) was only able to attain an ROC AUC of 0.57 (Additional file 2: Table S6).

Note that the distribution of ethnic subpopulations (e.g., European American, Irish, and British) across the WTCCC and GTEx cohorts was very similar, and thus unlikely a contributing factor to performance estimates (Additional file 3). Both the logistic regression model and the PRS methods significantly underperformed AVA,Dx on this same panel (ROC AUC = 0.76).

With all of its advantages, several limitations of our method remain.

First, AVA,Dx’s prediction power decreases when the exome sequences of the test panel, or the individual whose status is to be evaluated, share too few loci with the CD-train panel. There are two reasons for the difference in the covered loci—exome population of origin and sequencing quality. In case of the former, it is, arguably, not surprising that a genetic test that works for one population is not as good in, or may be not even applicable to, other populations, as is the case for other diseases (e.g., as for venous thromboembolism in AfricanAmericans vs. Caucasians56). At

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an even finer level, different types of CD may also not be properly evaluated with a single test, as is also the case, e.g., different subtypes of breast cancer57. Note, however, that AVA,Dx performs similarly well for the early- and late-onset CD individuals, whose exomes were part of the training panel; the possible difference in performance could not be evaluated further as the WTCCC panel had no annotations of time of onset. The difference in sequencing quality is an even more straightforward issue—missing variant calls decrease the method power. We estimate that sharing at least 58% of the training set variants (Additional file 2: Table S3) is sufficient for prediction ROC AUC of 0.69 (i.e., CD-test); although sharing more is better (i.e., ~ 80% shared in WTCCGTEX; ROC AUC = 0.76).

Importantly, also note that evaluating AVA,Dx performance on testing panels sequenced separately not only from the training set, but also from each other, is complicated by inter-test batch effects. That is, although we used ComBat to ameliorate the batch effects between the training panel and testing individuals, our procedure of removing batch effects for one individual at a time could not guarantee that testing panels would be non-differentiable by batch. We evaluated whether sequencing explicitly differentiates testing panels by checking their sequenced variant overlap; here, WTCCC and GTEx shared over 92% (981) of the variants in the AVA,Dx DKM gene set (of 1059 in WTCCC and 1026 in GTEx). These results suggest that sequencing differences between testing panels did not contribute significantly to the results of this study. However, more work with larger panels is necessary to evaluate the impact of batch effects on prediction performance.

Another limitation of AVA,Dx is its poor ability to recognize healthy people as healthy. The explanation for this observation is simple: our method aims to identify genetic patterns common to individuals affected by CD (a fairly welldefined panel), rather than those of healthy ones (an extremely wide set of people). Answering the latter question is akin to proving a negative—how can one be sure that the healthy people in our panel actually do not have and will never develop CD? Also note that the reliability of CD prediction is modulated by choosing a higher prediction threshold. Thus, people scoring above our strict cutoff are very likely to have CD; however, those that score just below it are termed “healthy,” which they

often are not. Thus, although AVA,Dx was better than random in identifying healthy people in our panel, we do not suggest using it for these purposes.

Our method is able to use less than 5% of the people normally involved in a GWAS study to identify disease genes and to make fairly accurate CD predictions for previously unseen individuals. At high AVA,Dx scores, our method is optimized for high precision, i.e., misclassifying few healthy individuals as sick; lower AVA,Dx recall at this cutoff, i.e., failing to identify many CD patients, suggests that there are multiple CD subtypes that have yet to be clinically established.

Notably, AVA,Dx is robust to differences in panels and in sequencing/filtering methods, making our approach potentially clinically useful going forward.

Furthermore, AVA,Dx-identified genes appear to be relevant to CD, as indicated by the matches of our pathways to known work, and yet significantly different from those highlighted by other methods. Thus, our method presents an orthogonal way for identifying disease-related genes, while avoiding the most severe research limitation—the requirement of a large study panel.

This finding is in line with the higher risk expectation of causal, rather than associated, variants58.

While a larger panel could improve performance, our results suggest that model training can also be performed using already existing panels. Note that GWAS are higher powered to stratify CD subtypes and better able to deal with ethnicity-driven differences. Most crucially, however, they can identify the disease-relevant non-coding variants. Thus, it is clear that future inclusion of the effects of regulatory, synonymous, and copy number variants is likely to improve AVA,Dx performance. Finally, we suggest that the AVA,Dx approach to model building is not limited to Crohn’s disease, but is rather applicable to a wide spectrum of genetically linked, potentially rare and complex, diseases.

Conclusions To summarize, we developed AVA,Dx, a tool that uses exome variant-caused gene functional changes to identify diseaserelated genes and make health status predictions. AVA,Dx can be used orthogonally for identifying disease-related genes. Larger panels and more comprehensive gene scoring schemes could potentially improve performance.

References on request

Clinical R&D 45 Hansa Biopharma receives positive CHMP opinion for IdefirixTM (imlifidase) for kidney transplant in EU Hansa Biopharma, the leader in immunomodulatory enzyme technology for rare IgG mediated diseases, have announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion, recommending conditional approval of IdefirixTM (imlifidase) for the desensitization treatment of highly sensitized adult kidney transplant patients with a positive crossmatch against an available deceased donor. Endorsement of the positive opinion by the European Commission is expected in the third quarter of 2020.

“We are very excited to receive a positive opinion from the CHMP. This brings hope to the thousands of highly sensitized patients across Europe waiting for a life-saving kidney transplant and takes Hansa Biopharma one important step closer to becoming a commercial stage biopharmaceutical company,” says Søren Tulstrup, President and CEO of Hansa Biopharma.

“Today’s decision by the CHMP further serves to validate the potential of Hansa Biopharma’s proprietary drug development engine to develop approvable immunomodulatory drug candidates for rare and serious diseases and comes at a time when we are significantly expanding our activities into autoimmune diseases, gene therapy and oncology.”

The Marketing Authorization Application for imlifidase in kidney transplant was accepted for review by the European Medicines Agency on Feb. 28, 2019 based on data from four completed phase 2 studies across Sweden, France and the United States. Imlifidase met all primary and secondary endpoints in each study.

Imlifidase was supported through EMA's PRIority MEdicines (PRIME) scheme, which provides early and enhanced scientific and regulatory support to medicines that have a particular potential to address patients' unmet medical needs. Imlifidase was granted eligibility to PRIME in May 2017.

In the US, following overall agreement with the FDA, Hansa Biopharma submitted a study protocol to the FDA on June 17, 2020. The randomized, controlled clinical study is planned to be initiated in Q4 this year and could support a future BLA

submission in the US by 2023, as communicated earlier. The Company aims to recruit 45 highly sensitized patients at 10-15 centers in the US for this study.

EPIDYOLEX® (cannabidiol) has been reclassified by the UK Home Office as a Schedule 5 drug GW Pharmaceuticals plc (Nasdaq: GWPH) ("GW", "the Company" or "the Group"), a world leader in discovering, developing and delivering regulatory approved cannabis-based medicines, have announced that the UK Home Office has reclassified EPIDYOLEX (cannabidiol) as a Schedule 5 drug. This change will take effect immediately in all four of the constituent nations of the UK – with Northern Ireland enacting separate legislation1 – and sees the medicine move from Schedule 2 to Schedule 5 under the Misuse of Drugs Regulations 2001.

"The decision to move EPIDYOLEX to a low level of control is an important one for patients, their families, healthcare professionals, pharmacists and the NHS as a whole – reducing costs and ensuring the medicine can be dispensed more easily," said Chris Tovey, GW's Chief Operating Officer. "The extensive pre-clinical and clinical data that GW developed to support the medicine's approval by regulatory authorities was pivotal to this important schedule change, and we would like to thank the MHRA, ACMD and Home Office for scrutinising this data and making this change in such a short timeframe. We remain committed to expanding the high-quality evidence base for cannabis-based medicines and securing further regulatory approvals because doing so is in the interests of patients and healthcare professionals and can support further rescheduling."

The ACMD and its Technical Committee recommended the schedule change to Kit Malthouse MP, Minister of State for Crime and Policing, on 29 January 2020.

This followed the submission of a written dossier and oral presentation from the MHRA, which drew on the substantial data package developed by GW as part of the medicine's review and subsequent approval by the regulatory authorities in September 2019. The medicine is approved in the EU for adjunctive therapy of seizures associated with Lennox Gastaut syndrome or Dravet syndrome, in conjunction with clobazam, for patients from 2 years of age and older.

In its recommendation to the

Minister, the ACMD cited the "low risk of abuse potential, low risk of dependency and low risk of diversion" as reasons for the reclassification from a schedule 2 controlled drug to a schedule 5 controlled drug.2 The ACMD also cautioned that GW's medicine is "distinct from other commercially available CBD containing supplements that have not sought marketing authorisation as a medicine" and that the schedule change therefore applies exclusively to EPIDYOLEX. Sanofi and Translate Bio expand collaboration to develop mRNA vaccines across all infectious disease areas Sanofi Pasteur, the vaccines global business unit of Sanofi, and Translate Bio (NASDAQ: TBIO), a clinical-stage messenger RNA (mRNA) therapeutics company, have agreed to expand their existing 2018 collaboration and license agreement to develop mRNA vaccines for infectious diseases.

The expansion of this agreement will further unite Translate Bio's expertise and knowledge from more than 10 years of mRNA research and development with Sanofi's leadership in vaccine research and development.

Under the expansion agreement, Translate Bio will receive a total upfront payment of $425 million, consisting of a $300 million cash payment and a private placement common stock investment of $125 million at $25.59 per share representing a 50 percent premium to the 20-day moving average share price prior to signing. Translate Bio will also be eligible for potential future milestones and other payments up to $1.9 billion, including $450 million of milestones under the 2018 agreement. Of these potential milestones and other payments, approximately $360 million are anticipated over the next several years, inclusive of COVID-19 vaccine development milestones. In addition, Translate Bio is also eligible to receive tiered royalty payments based upon worldwide sales of the developed vaccines. Sanofi Pasteur will pay for all costs during the collaboration term.

Under this agreement Sanofi Pasteur will receive exclusive worldwide rights for infectious disease vaccines.

"As all eyes are on prevention of infectious disease through vaccines, this is a pointed moment in time where we are called upon to seek innovative ways to protect public health," said Thomas Triomphe, Executive Vice President, Sanofi Pasteur.

"We are excited by the novel

technology and expertise Translate Bio brings, and we believe that adding this mRNA platform to our vaccines development capabilities will help us advance prevention against current and future infectious diseases."

Under the collaboration, Translate Bio is using its mRNA platform to discover, design and manufacture vaccine candidates and Sanofi Pasteur is providing its deep vaccine expertise to advance vaccine candidates into and through further development.

Translate Bio will also transfer technology and processes to allow Sanofi Pasteur to develop and manufacture mRNA vaccines for infectious diseases.

Tiziana Granted First-Ever Patent on a Transformational Technology for Oral Delivery of all Anti-CD3 Monoclonal Antibodies for Treatment of Human Diseases Tiziana Life Sciences plc (Nasdaq: TLSA; AIM: TILS) ("Tiziana" or the "Company"), a biotechnology company focused on innovative therapeutics for oncology, inflammation and infectious diseases, have announced that the United States Patent and Trademark Office ("USPTO") has granted a patent covering its proprietary platform technology for the oral administration of Foralumab, its proprietary fully human monoclonal antibody, and all other anti-CD3 monoclonal antibodies (mAb). The CD3 (cluster of differentiation 3) is a protein complex on T-cells, which is important for regulation of immune system. The patent will be issued by the USPTO on 23 June 2020.

"The issuance of this first-ever patent on formulation for oral administration of mAbs is a very exciting and timely development, as it facilitates a transformational avenue for immunotherapies," commented Dr. Howard L. Weiner, Chairman of Tiziana's Scientific Advisory Board, Robert L. Kroc Professor of Neurology at the Harvard Medical School, Director and Founder of the Partners Multiple Sclerosis Center and Co-Director of the Ann Romney Center for Neurologic Diseases at the Brigham and Women's Hospital. "We also recently successfully demonstrated that nasally-administered Foralumab is not only well tolerated but also produced desirable immunological responses. In addition, both oral and nasal administration routes are physiologic approaches to stimulate the mucosal immune system to induce disease modifying benefits, while minimizing the severe

HOSPITALPROFESSIONALNEWS.IE | HPN • JUNE/JULY 2020

46 Clinical R&D toxicities commonly associated with the traditional intravenous administration of anti-CD3 mAbs." "The granting of this patent on first-in-class formulation technology allows us to work on bringing patients the first nonintravenous or subcutaneous treatment with antibodies to treat major gastrointestinal and neurodegenerative diseases such as Crohn's Disease, proMS and Alzheimer's disease.

We believe development of the alternative administration routes of antibodies such as oral, nasal and inhalation could potentially be transformational for immunotherapies," added Gabriele Cerrone, chairman and founder of Tiziana.

The patent titled "Anti-CD3 formulations; patent No. 10,688,186, Inventor: Kunwar Shailubhai", is the first-ever to be granted on anti-CD3 formulations and covers oral administration with lyophilized and stabilized free-flowing powder of Foralumab or any other anti-CD3 mAb, encapsulated in enteric-coated capsules, for treatment of human diseases. In addition, the stabilized liquid formulation of Foralumab and other anti-CD3 mAbs for nasal administration is also covered in this patent.

These formulation technologies have the potential to transform immunotherapies, which currently can only be administered through intravenously or subcutaneously.

Tiziana previously reported the successful completion of a Phase 1 trial utilizing oral administration of Foralumab, which was designed to evaluate its safety and tolerability in healthy subjects. The trial was conducted at Brigham and Women's Hospital, Harvard Medical School, Boston, Mass., and indicated that oral administration of Foralumab was well tolerated up to a 5 mg dose (https://www.tizianalifesciences. com/news-item?s=2020-0109-tiziana-reports-phase-1clinical-data-demonstrating-oraltreatment-with-foralumab-a-fullyhuman-anti-cd3-monoclonalantibody-is-well-toleratedin-healthy-volunteers). The Company plans to move forward with further development of orally administered Foralumab for evaluation in moderate-tosevere patients with Crohn's Disease. Additionally, Tiziana previously reported the successful completion of a Phase 1 study evaluating safety and analysis of biomarkers for clinical activity of nasally administered stabilized solution of Foralumab (https:// www.tizianalifesciences.com/ news-item?s=2018-11-28tiziana-announces-initiation-of-

phase-1-clinical-trial-with-nasaladministration-of-foralumab-afully-human-anti-cluster-definition3-monoclonal-antibody-anticd3-mab-in-healthy-volunteers).

A Phase 2 trial in patients with progressive multiple sclerosis will commence shortly. Importantly, in both clinical studies, the severe toxicities commonly associated with intravenous administration of anti-CD3 mAbs were not observed with oral or nasal administration of Foralumab.

Sanofi announces positive long-term efficacy and safety data for fitusiran from interim analysis of Phase 2 extension study in people with hemophilia A and B, with or without inhibitors New data exploring the efficacy and safety of fitusiran, an investigational once-monthly, subcutaneously administered RNA interference (RNAi) therapy for the treatment of hemophilia A and B, with or without inhibitors, have been shared in a late-breaking presentation at the World Federation of Hemophilia Virtual Summit.

Long-term interim results from the Phase 2 open-label extension (OLE) study reinforce fitusiran's potential to restore hemostatic balance and to lower annualized bleed rates (ABRs) over a period up to 57 months.

• Monthly subcutaneous dosing with fitusiran, in patients with hemophilia A and B, with or without inhibitors, demonstrated sustained antithrombin lowering (a reduction of around 75% from baseline), resulting in median peak thrombin values at the lower end of the range observed in healthy volunteer participants.

• Low overall median ABR of 0.84. The median ABR in the non-inhibitor subgroup was 1.01 compared to pre-study median ABRs of 2.0 for patients previously on prophylactic treatment and 12.0 for patients previously on demand. In the inhibitor subgroup, median ABRs were 0.44 compared to pre-study median ABRs of 42.0.

• Low overall spontaneous bleeds (overall median of 0.38).

Median spontaneous ABRs by subgroup were 0.33 (noninhibitor) and 0.39 (inhibitors).

• No anti-drug antibody formation was detected Genmab Announces Very Favorable Topline Results from Phase 2 Clinical Trial of Tisotumab Vedotin in Recurrent or Metastatic Cervical Cancer

"These new interim data support the potential of fitusiran to have a transformative impact on hemophilia management with the aim to provide patients with consistent bleed protection and only once monthly subcutaneous dosing," said Dietmar Berger, Global Head of Development, Sanofi. "We are continuing to advance our portfolio of factor and non-factor therapies that could offer people with hemophilia a broad range of therapeutic options to fit their individual needs. We continue to investigate the clinical profile of fitusiran in our Phase 3 ATLAS program with results expected in the first half of 2021 and look forward to offering this novel therapy to patients globally."

Genmab A/S (Nasdaq: GMAB) have announced very favorable topline results from the Phase 2 single-arm clinical trial known as innovaTV 204 evaluating tisotumab vedotin administered every three weeks for the treatment of patients who have relapsed or progressed on or after prior treatment for recurrent or metastatic cervical cancer. Results from the trial showed a 24 percent confirmed objective response rate (ORR) by independent central review (95% Confidence Interval: 15.9% - 33.3%) with a median duration of response (DOR) of 8.3 months.

The most common treatmentrelated adverse events (greater than or equal to 20 percent) included alopecia, epistaxis (nose bleeds), nausea, conjunctivitis, fatigue and dry eye. The data will be submitted for presentation at an upcoming medical meeting.

The Phase 2 OLE study evaluates the long-term efficacy and safety of fitusiran in patients with moderate or severe hemophilia A and B, with or without inhibitors, who had participated in a previous study of fitusiran. This data evaluated 34 enrolled patients who received monthly fixed 50mg or 80mg doses of fitusiran and were followed for a period up to 4.7 years, with a median exposure of 2.6 years. At the data cutoff (March 10, 2020), interim results showed:

Tisotumab vedotin is an investigational antibody-drug conjugate (ADC) directed to tissue factor, which is expressed on cervical cancer and can promote tumor growth, angiogenesis and metastases.1 Standard therapies for previously treated recurrent and/or metastatic cervical cancer generally result in limited objective response rates of typically less than 15 percent with median overall survival ranging from 6.0 to 9.4 months, in an allcomers population.1-8 Tisotumab

JUNE/JULY 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

vedotin is being developed in collaboration with Seattle Genetics.

"After treatment with first-line chemotherapy regimens, there is a high unmet need for new effective and tolerable treatment options for women with advanced cervical cancer, regardless of biomarkers and histology," said Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab.

"These promising topline data from innovaTV 204 will be the basis of further engagement with the U.S. FDA as we continue to progress and expand our tisotumab vedotin development program in solid tumors with our partner."

Additional clinical trials of tisotumab vedotin are currently enrolling patients, including in combination with pembrolizumab, carboplatin or bevacizumab, and with a weekly dosing schedule in patients with locally advanced or metastatic cervical cancer.

Tisotumab vedotin is also being evaluated in other tissue factor expressing tumor types, including ovarian and other solid tumors.

RedHill Biopharma Receives Approval for COVID-19 Phase 2/3 Study with Opaganib in the UK RedHill Biopharma Ltd. (Nasdaq: RDHL) ("RedHill" or the "Company"), a specialty biopharmaceutical company, have announced that the UK Medicines & Healthcare products Regulatory Agency (MHRA) has approved the Company's Clinical Trial Authorization (CTA) application to commence a Phase 2/3 study evaluating opaganib (Yeliva®, ABC294640)1 in patients hospitalized with severe SARS-CoV-2 infection (the cause of COVID-19) and pneumonia.

RedHill has also submitted CTA applications for this study in Russia and Italy and plans to expand the study to additional countries.

Mark L. Levitt, M.D., Ph.D., Medical Director at RedHill, stated, "This timely approval from the UK regulatory authority for the Phase 2/3 study with opaganib comes as the global infection rates continue to grow and there remains a serious unmet medical need for a safe and effective treatment for COVID-19. We are rapidly advancing our COVID-19 program with opaganib, including the recently initiated Phase 2a study in leading U.S. centers."

The multi-center, randomized, double-blind, parallel-arm, placebo-controlled Phase 2/3 study is set to enroll up to 270 subjects with severe

Clinical R&D 47 COVID-19 pneumonia requiring hospitalization and treatment with supplemental oxygen.

Subjects will be randomized at a 1:1 ratio to receive either opaganib or placebo, along with standard-of-care therapy. The primary endpoint of the study is to evaluate the proportion of patients requiring intubation and mechanical ventilation by Day 14. An unblinded futility only interim analysis will be conducted by an independent data safety monitoring board (DSMB) when approximately 100 subjects have been evaluated for the primary endpoint. The study is planned to be conducted in clinical sites across Italy, the UK, Russia and additional countries.

In parallel, RedHill has initiated enrollment for a randomized, double-blind, placebocontrolled Phase 2a clinical study with opaganib in the U.S. (NCT04414618). This study is set to enroll up to 40 patients with severe COVID-19 pneumonia requiring hospitalization and supplemental oxygen. This clinical trial is not powered for statistical significance.

Tiziana Life Sciences Announces Agreement with STC Biologics This proprietary inhalation technology for direct delivery of mAbs or other small molecule drugs such as Remdesivir® (Roche) to lungs could potentially be a transformational therapy for developing a rapid treatment for COVID-19 Tiziana Life Sciences plc (Nasdaq: TLSA / AIM: TILS) ("Tiziana" or the "Company"), a clinical stage biotechnology company developing targeted drugs for cancer, inflammatory diseases and COVID-19, has announced the execution of an agreement with STC Biologics, Inc. ("STC") for GMP manufacturing of TZLS501, an anti-IL-6 receptor (anti-IL6R) monoclonal antibody (mAb) acquired from Novimmune in 2017, currently in agreement with Bristol Myers Squibb (BMS).

Tiziana is simultaneously developing an inhalation technology, in collaboration with Sciarra Laboratories, for the direct delivery of TZLS-501 into the lungs using a handheld inhaler or nebulizer for treatment of patients with COVID-19. The proprietary novel technology to administer TZLS-501 directly into the nasal passages or lungs by inhaler or nebulizer has potentially significant clinical advantages for the treatment of COVID-19 patients.

The Company recently submitted

a patent application for the inhalation delivery of anti-IL6Rmonoclonal antibody for the treatment of COVID-19.

TZLS-501, a unique and bestin-class anti-IL-6R mAb, follows a dual mechanism by not only blocking downstream signaling pathways from membrane-bound and soluble IL-6 receptors, but it also rapidly depletes bloodstream levels of IL-6, the major culprit for cytokine release syndrome (CRS) in lungs of COVID-19 patients. In receptor binding assays, TZLS-501 is considerably more potent than the other anti-IL-6R mAb in this class, such as Actemra® (Roche)1,2. These biochemical features, differentiating TZLS-501 from other mAbs in this class, offer potential distinctive clinical advantages in effecting a rapid suppression of the cytokine storm at much lower doses.

The proprietary inhalation technology for direct delivery of mAbs or other small molecule drugs such as Remdesivir® (Roche) to lungs could potentially be a transformational therapy for developing a rapid treatment of COVID-19 "We are aggressively advancing GMP manufacturing of TZLS-501 concurrently with the development of inhalation technology using a hand-held nebulizer and safety toxicology studies in cynomolgus monkeys. Our objective is to submit an Investigational New Drug (IND) Application in the first quarter of 2021 for the treatment of COVID-19 patients," said Kunwar Shailubhai, Ph.D., CEO and CSO of Tiziana Life Sciences.

"The initiation of GMP manufacturing of TZLS-501 with STC is a timely step forward toward expediting development of a potentially innovative treatment for COVID-19 patients. We are very excited and well positioned to accelerate the development of TZLS-501 for COVID-19 patients in such extraordinary times," added Dr. Magdalena Leszczyniecka, President and CEO of STC Biologics. "Our state-of-the-art single use production facility, highly crosstrained experienced personnel, and nimble decision-making has provided unprecedented speed to clinic in prior GMP campaigns.

Together with a strong track record of pharmaceutical, regulatory and process development know-how, we are uniquely positioned to advance TZLS-501 to the clinic."

Trans-signaling Pathways by Differentially Manipulating the Assembly of the IL-6 Signaling Complex. J Biol Chem. 2015 Nov 6; 290(45): 26943–26953.

2. Chaolin Huang, MD., et al., Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.

The Lancet, volume 395, pages 497-506. 2020. Published January 24, 2020.

3.Tiziana Lifesciences Press Release: https://www. tizianalifesciences.com/ news-item?s=2019-09-10tiziana-reports-phase-1-clinicaldata-demonstrating-nasaltreatment-with-foralumab-waswell-tolerated-and-producedpositive-trend-in-biomarkersof-immunomodulation-andanti-inflammation-in-healthyvolunteers Covid Tracker App Data Protection Impact Assessment and source code The Department of Health and the Health Service Executive have today (Friday, June 26th) published several important documents as part of our ongoing commitment to openness and transparency in the development of the Covid Tracker App for Ireland.

The Data Protection Impact Assessment, the source code, the Product Explainer for the Covid Tracker App, and a series of app design and development reports are available on the HSE website here https://www.hse.ie/!DW3Q7R As the country reopens, contact tracing and the early identification of symptoms, will become increasingly important as more people are visiting family and friends, exercising, socialising, shopping, returning to work and using public transport.

The Covid Tracker App will allow each individual to play an important part in controlling COVID-19, helping everyone to stay safe and protect each other.

The app will record if a user is in close contact with another user by exchanging anonymous codes that are held on the users’ phones.

Cited References

People who test positive for coronavirus will be able to choose if they want to anonymously alert other app users who they have been in close contact with. In this way the app will augment the existing testing and tracing operation and enable the notification of close contacts that are unknown to each other.

1. Lacroix, M. et al., Novel Insights into Interleukin 6 (IL-6) Cis- and

The app will also allow the user to anonymously record information

about how they feel every day.

The symptom tracker has the potential to generate valuable national data relevant to COVID-19. The accurate reporting of the timing of the first onset of symptoms will improve the speed and the accuracy of the tracing process.

In line with data protection law, the processing of data will be limited to this stated purpose. All personal data that is processed is kept to an absolute minimum.

Users can choose to delete the app at any time and have full control over what information they share through the app. Further, a governance commitment is in place to dismantle the operation of the app once the COVID-19 crisis is over.

Chief Information Officer (CIO) of the HSE Fran Thompson said, “The design of Covid Tracker App has been informed by a robust development and testing programme. The app development process here in Ireland has been led by the HSE and the Department of Health, in collaboration with the Government Chief Information Officer and An Garda Síochána, together with technical partners from the Irish private sector (Expleo, Nearform, Information Security Assurance Services Ltd. (ISAS), and EdgeScan) and scientific partners from Science Foundation Ireland. Results from our testing programme have shown that the app was able to accurately detect 72% of close contacts using the Google Apple API.” Supporting the development of the technology, a programme of public health research has been completed to ensure that the app is easy to use, protects privacy, and supports users over time. The findings of independent research the recent Lero study published this week by Science Foundation Ireland (SFI) found that 82% of the population said that they would be willing to install an app for contact tracing.

This work at a national level has been situated in an unprecedented global collaboration between governments, industry and the scientific community. The Irish app, designed employing the decentralised model, allows us to align fully with the privacy principles and public health guidance issued by the EU Commission, the OECD, WHO and the European Centre for Disease Prevention and Control.

HOSPITALPROFESSIONALNEWS.IE | HPN • JUNE/JULY 2020

You know best how to protect your patients

EXTRA

‘GRANDAD’ MOMENTS THANKS TO THE PROTECTION YOU PROVIDE FOR YOUR PATIENTS

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 of the Summary of Product Characteristics (SmPC) for how to report adverse reactions. Xarelto 2.5 mg/ 10 mg / 15 mg / 20 mg film-coated tablets (rivaroxaban). Refer to full SmPC before prescribing. Presentation: Film-coated tablet containing 2.5 mg / 10 mg / 15 mg / 20 mg rivaroxaban.

Contains lactose. Indications: 2.5 mg: Prevention of atherothrombotic events in adult patients after an acute coronary syndrome (ACS) with elevated cardiac biomarkers, co-administered with acetylsalicylic acid (ASA) alone or with ASA plus clopidogrel or ticlopidine. Prevention of atherothrombotic events in adult patients with coronary artery disease (CAD) or symptomatic peripheral artery disease (PAD) at high risk of ischaemic events, co-administered with ASA. 10 mg: Prevention of venous thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery. Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) and prevention of recurrent DVT and PE in adults. 15 mg/20 mg: Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation with one or more risk factors, such as congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, prior stroke or transient ischaemic attack. Treatment of DVT and PE, and prevention of recurrent DVT and PE in adults.

Special populations: (for 15 mg / 20 mg only): specific dose recommendations apply for patients with moderate to severe renal impairment and in case of DVT/PE-patients only if the patient’s assessed risk for bleeding outweighs the risk for recurrent DVT/PE. Patients undergoing cardioversion: Xarelto can be initiated or continued in patients who may require cardioversion. Patients with non-valvular atrial fibrillation who undergo PCI (percutaneous coronary intervention) with stent placement: There is limited experience of a reduced dose of 15 mg Xarelto once daily (or 10 mg Xarelto once daily for patients with moderate renal impairment [creatinine clearance 30-49 ml/min]) in addition to a P2Y12 inhibitor for a maximum of 12 months in patients with non-valvular atrial fibrillation who require oral anticoagulation and undergo PCI with stent placement. Dosage and Administration: ACS: Recommended dose is 2.5 mg twice daily. Patients should also take a daily dose of 75 - 100 mg acetylsalicylic acid (ASA) or a daily dose of 75 - 100 mg ASA in addition to either a daily dose of 75 mg clopidogrel or a standard daily dose of ticlopidine.

Treatment should be regularly evaluated in the individual patient weighing the risk for ischaemic events against the bleeding risks. Extension of treatment beyond 12 months should be done on an individual patient basis as experience up to 24 months is limited. Treatment with Xarelto should be started as soon as possible after stabilisation of the ACS event (including revascularisation procedures); at the earliest 24 hours after admission to hospital and at the time when parenteral anticoagulation therapy would normally be discontinued. CAD/PAD: Recommended dose is 2.5 mg twice daily. Patients taking Xarelto 2.5 mg twice daily should also take a daily dose of 75 - 100 mg ASA. Duration of treatment should be determined for each individual patient based on regular evaluations and should consider the risk of thrombotic events versus the bleeding risks. In patients with an acute thrombotic event or vascular procedure and a need for dual antiplatelet therapy, the continuation of this treatment should be evaluated depending on the type of event or procedure and antiplatelet regimen. Safety and efficacy of Xarelto 2.5 mg twice daily in combination with ASA plus clopidogrel/ticlopidine has only been studied in patients with recent ACS. Dual antiplatelet therapy has not been studied in combination with Xarelto 2.5 mg twice daily in patients with CAD/PAD. Renal impairment: Limited clinical data for patients with severe renal impairment (creatinine clearance 15 - 29 ml/min) indicate that rivaroxaban plasma concentrations are significantly increased.

Therefore, Xarelto is to be used with caution in these patients. Use is not recommended in patients with creatinine clearance < 15 ml/min. No dose adjustment is necessary in patients with mild renal impairment (creatinine clearance 50 - 80 ml/min) or moderate renal impairment (creatinine clearance 30 - 49 ml/min).

Hepatic impairment: Xarelto is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C. Paediatric population: The safety and efficacy of Xarelto in children aged 0 to 18 years have not been established. No data are available. Therefore, Xarelto is not recommended for use in children below 18 years of age. Prevention of VTE in elective hip or knee replacement surgery: Recommended dose is 10 mg

PP-XAR-IE-0153-3

rivaroxaban taken orally once daily. The initial dose should be taken 6 to 10 hours after surgery, provided that haemostasis has been established. Duration of treatment depends on the individual risk of the patient for VTE which is determined by the type of orthopaedic surgery. For patients undergoing major hip surgery, treatment duration of 5 weeks is recommended. For major knee surgery, treatment duration of 2 weeks is recommended. Prevention of stroke and systemic embolism: The recommended dose is 20 mg once daily, which is also the recommended maximum dose. Treatment of DVT, treatment of PE and prevention of recurrent DVT and PE: The recommended dose for the initial treatment of acute DVT or PE is 15 mg twice daily for the first three weeks followed by 20 mg once daily for the continued treatment and prevention of recurrent DVT and PE. When extended prevention of recurrent DVT and PE is indicated (following completion of at least 6 months therapy for DVT or PE), the recommended dose is 10 mg once daily. In patients in whom the risk of recurrent DVT or PE is considered high, such as those with complicated comorbidities, or who have developed recurrent DVT or PE on extended prevention with Xarelto 10 mg once daily, a dose of 20 mg once daily should be considered. Renal impairment: No dose adjustment is necessary in patients with mild renal impairment. Xarelto is not recommended in patients with creatinine clearance < 15 mL/min. Xarelto is to be used with caution in patients with creatinine clearance 15-29 mL/min.

Prevention of VTE in elective hip or knee replacement surgery: no dose adjustment is necessary in patients with moderate renal impairment (creatinine clearance 30 - 49 ml/min). Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation: In patients with moderate or severe renal impairment, the recommended dose is reduced to 15 mg once daily. Treatment of DVT, treatment of PE and prevention of recurrent DVT and PE: No dose adjustment is considered necessary in moderate to severe renal impairment; although when the recommended dose is 20 mg once daily, a reduced dose of 15mg once daily should be considered if the patient’s assessed risk for bleeding outweighs the risk for recurrent DVT and PE. When the recommended dose is 10 mg once daily, no dose adjustment from the recommended dose is necessary. Hepatic impairment: Contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk, including cirrhotic patients with Child Pugh B and C. Contraindications: 2.5 mg only: Concomitant treatment of ACS with antiplatelet therapy in patients with a prior stroke or a transient ischaemic attack (TIA); concomitant treatment of CAD/PAD with ASA in patients with previous haemorrhagic or lacunar stroke, or any stroke within a month. 2.5 mg/ 10 mg/ 15 mg/ 20 mg: Hypersensitivity to the active substance or any of the excipients; active clinically significant bleeding; lesion or condition if considered a significant risk for major bleeding; concomitant treatment with any other anticoagulants except under specific circumstances of switching anticoagulant therapy or when unfractionated heparin is given at doses necessary to maintain an open central venous or arterial catheter; hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C; pregnancy and breast feeding. Warnings and Precautions: Clinical surveillance in line with anticoagulation practice is recommended throughout treatment. Xarelto should be discontinued if severe haemorrhage occurs. Increasing age may increase haemorrhagic risk. Xarelto should be discontinued at the first appearance of a severe skin rash, or any other sign of hypersensitivity in conjunction with mucosal lesions. Not recommended: in patients with severe renal impairment (creatinine clearance <15 ml/min); in patients receiving concomitant systemic treatment with strong concurrent CYP3A4- and P-gp-inhibitors, i.e. azole-antimycotics or HIV protease inhibitors; in patients with increased bleeding risk; in patients receiving concomitant treatment with strong CYP3A4 inducers unless the patient is closely observed for signs and symptoms of thrombosis; for patients with a history of thrombosis diagnosed with antiphospholipid syndrome; Xarelto should not be used for thromboprophylaxis in patients having recently undergone transcatheter aortic valve replacement (TAVR); not recommended due to lack of data: 2.5 mg: treatment combination with antiplatelet agents other than ASA and clopidogrel/ticlopidine; 2.5 mg/ 10 mg/ 15 mg/ 20 mg: in patients below 18 years of age, in patients concomitantly treated with dronedarone, in patients with prosthetic heart valves, 10 mg/ 15 mg/ 20 mg: in patients with PE who are haemodynamically unstable or may receive thrombolysis or pulmonary embolectomy. Use with caution: in conditions with increased risk of haemorrhage; in patients with severe renal impairment (creatinine

clearance 15 - 29 ml/min); in patients with renal impairment (Xarelto 15 mg/20 mg) or with moderate renal impairment (creatinine clearance 30 - 49 ml/min) (Xarelto 2.5 mg/10 mg) concomitantly receiving other medicinal products which increase rivaroxaban plasma concentrations; in patients treated concomitantly with medicinal products affecting haemostasis; when neuraxial anaesthesia or spinal/epidural puncture is employed. In patients at risk of ulcerative gastrointestinal disease prophylactic treatment may be considered. Although treatment with rivaroxaban does not require routine monitoring of exposure, rivaroxaban levels measured with a calibrated quantitative anti-Factor Xa assay may be useful in exceptional situations. Contains lactose. 2.5 mg only: Use with caution in patients ≥75 years of age or with lower body weight (<60 kg); in CAD patients with severe symptomatic heart failure. Patients on treatment with Xarelto and ASA or Xarelto and ASA plus clopidogrel/ticlopidine should only receive concomitant treatment with NSAIDs if the benefit outweighs the bleeding risk. Interactions: Use of Xarelto is not recommended in patients receiving concomitant systemic treatment with azole-antimycotics (such as ketoconazole, itraconazole, voriconazole and posaconazole) or HIV protease inhibitors (e.g. ritonavir).

These active substances are strong inhibitors of both CYP3A4 and P-gp. The interaction with clarithromycin, erythromycin or fluconazole is likely not clinically relevant in most patients but can be potentially significant in high-risk patients. Co-administration of Xarelto with dronedarone should be avoided. Care is to be taken if patients are treated concomitantly with any other anticoagulants. Care is to be taken if patients are treated concomitantly with NSAIDs (including ASA) and platelet aggregation inhibitors because these medicinal products typically increase the bleeding risk. The possibility may exist that patients are at increased bleeding risk in case of concomitant use with SSRIs or SNRIs. Concomitant use of strong CYP3A4 inducers (such as rifampicin, phenytoin, carbamazepine, phenobarbital or St. John’s Wort) should be avoided as they may lead to reduced rivaroxaban plasma concentration unless the patient is closely observed for signs and symptoms of thrombosis. Clotting parameters (e.g. PT, aPTT, HepTest) are affected as expected by the mode of action of rivaroxaban. Fertility, Pregnancy and Lactation: Pregnancy: Xarelto is contraindicated during pregnancy. Breast-feeding: Xarelto is contraindicated during breast-feeding; a decision must be made to discontinue breast-feeding or discontinue/abstain from therapy. Fertility: No specific studies with rivaroxaban in humans have been conducted to evaluate effects on fertility. In a study on male and female fertility in rats, no effects were seen. Driving and using machines: Xarelto has minor influence on the ability to drive and use machines. Patients experiencing adverse reactions like syncope and dizziness should not drive or use machines. Undesirable effects: Common: anaemia, dizziness, headache, eye haemorrhage, hypotension, haematoma, epistaxis, haemoptysis, gingival bleeding, gastrointestinal tract haemorrhage, gastrointestinal and abdominal pains, dyspepsia, nausea, constipation, diarrhoea, vomiting, increase in transaminases, pruritus, rash, ecchymosis, cutaneous and subcutaneous haemorrhage, pain in extremity, urogenital tract haemorrhage (menorrhagia very common in women < 55 years treated for DVT, PE or prevention of recurrence), renal impairment, fever, peripheral oedema, decreased general strength and energy, post-procedural haemorrhage, contusion, wound secretion. Uncommon: thrombocytosis, thrombocytopenia, allergic reaction, dermatitis allergic, angioedema, allergic oedema, cerebral and intracranial haemorrhage, syncope, tachycardia, dry mouth, hepatic impairment, urticaria, haemarthrosis, feeling unwell, increases in: bilirubin, blood alkaline phosphate, GGT, LDH, lipase, amylase.

Rare: jaundice, bilirubin conjugated increased, cholestasis, hepatitis (including hepatocellular injury), muscle haemorrhage, localised oedema, vascular pseudoaneurysm (uncommon in prevention therapy in ACS following percutaneous coronary intervention). Very Rare: Anaphylactic reactions including anaphylactic shock, Stevens-Johnson syndrome/ toxic epidermal necrolysis, DRESS syndrome. Frequency not known: compartment syndrome secondary to a bleeding, renal failure/ acute renal failure secondary to a bleeding. Prescription only. Marketing Authorisation Holder: Bayer AG, 51368 Leverkusen, Germany. MA numbers: EU/1/08/472/001-024. Further information available from: Bayer Ltd., The Atrium, Blackthorn Road, Dublin 18. Tel: 01 2163300. Date of Preparation: 07/2019